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MacLeod, Amanda S

Overview:

The new lab website can be found here: http://sites.duke.edu/macleodlab/

If you are interested in joining our laboratory, please contact Amanda MacLeod (amanda.macleod@duke.edu).

Our lab investigates surveillance and repair functions in the skin. Within this broad research area, we focus on immune regulation and modulation during skin injury, infection, and cancer.

Skin is an active immune organ and comprises not only keratinocytes, but also harbors tissue-resident T cells, dendritic cells, macrophages and other immune cells. This interplay of innate and adaptive immune cells facilitates surveillance and repair functions in the skin under homeostatic and challenged conditions.

I. Immune regulation and modulation during skin injury and infection

Damage to the skin through physical injury and microbes initiates release of multiple pro-inflammatory cytokines and mediators including IL-17, extracellular ATP, nucleic acids, NO, as well as antimicrobial peptides and proteins. Upon skin injury, inflammatory immune responses are aimed at clearing microbial contaminations before a repair program can subsequently facilitate wound closure. However, prolonged inflammation is detrimental and mediates tissue damage and is considered a major pathogenic factor for the development of chronic non-healing wounds and may be a trigger for auto-inflammatory skin diseases such as psoriasis. Therefore, fine regulation of the cutaneous immune response is critical to maintain skin barrier function and protection upon injury and infection. The focus of our laboratory is on identifying and characterizing such key factors that regulate innate and adaptive immunity in the skin. In particular, we focus on the regulation of innate antimicrobial peptides and proteins which provide a natural protection against pathogens. Amongst those molecules, we have identified taht antiviral proteins are abundantly expressed and induced in the skin. We use interdisciplinary approaches, including molecular and cellular biology approaches, human and murine wound, infection and inflammation model systems to study how host factors drive skin barrier immunity.

II. Mechanisms of immune escape in human squamous cell carcinoma

Despite an existing complex network of immune surveillance mechanisms in human skin, cutaneous squamous cell carcinoma (SCC) is one of the most prevalent cancers in humans. Excessive UV exposure, several chemicals (incurred by tobacco use or during military service), immunosuppression (upon organ transplantation) as well as chronic non-healing wounds are major risk factors for SCC. Our goal is to define immune surveillance and escape mechanisms present in the human SCC microenvironment to ultimately identify novel targets for immunotherapy. In particular, we are interested in the role of skin-resident T cell and DC/macrophage function and our goal is to understand how SCC hijacks immune cell-mediated danger signals and effector molecules to shut off protective immunity. Furthermore, we seek to understand the underlying mechanisms of how immunosuppressive treatments used in transplant organ patients selectively alter skin immunity to promote immune tolerance. A combination of genome-wide interrogation of gene expression in different SCC patient populations, and use of knockout mouse models and human primary cells and tissues will dissect the contribution of key molecules in skin immune function and escape.

III. Development of non-invasive skin disease detection assays

In collaborative efforts with the Duke Center for Genomic and Computational Biology, Integrative Genomic Analysis Shared Resource, and the Duke Dermatology Clinic we aim to identify skin-disease specific biomarker features that allow the development of non-invasive disease detection assays. Such approach of diagnosing skin diseases is of extremely high clinical and translational value.


Complete List of Published Work can be found here:

http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/47851812/?sort=date&direction=descending


Her maiden name Büchau was used prior to MacLeod.

Positions:

Associate Professor in Dermatology

Dermatology
School of Medicine

Assistant Professor in the Department of Immunology

Immunology
School of Medicine

Assistant Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

M.D. 2005

M.D. — Heinrich Heine University Düsseldorf (Germany)

News:

10 Weeks, and Research Gets Under Your Skin

October 07, 2015 — Duke Translational Medicine Institute

Grants:

Dynamic Control of Innate Antiviral Immunity in Skin Homeostasis and Inflammation

Administered By
Dermatology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 11, 2018
End Date
April 30, 2023

Biasing CXCR3 Signaling to Modulate the Inflammatory Response

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 20, 2017
End Date
June 30, 2022

Medical Scientist Training Program

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1997
End Date
June 30, 2022

Immunomodulatory Biomaterials via Peptide and Protein Self-Assembly

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 01, 2009
End Date
May 31, 2022

Immunotherapy to combat skin infections

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 23, 2019
End Date
March 31, 2020

Targeting Immune Dysregulation in Psoriasis

Administered By
Dermatology
Role
Principal Investigator
Start Date
March 03, 2017
End Date
January 31, 2020

IL-27 in skin host defense and regeneration

Administered By
Dermatology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 15, 2017
End Date
July 31, 2019

Role of IL-27 signaling in cutaneous regeneration and host defense

Administered By
Dermatology
AwardedBy
Dermatology Foundation
Role
Principal Investigator
Start Date
July 01, 2017
End Date
September 01, 2018

ATP in Skin Immunity

Administered By
Dermatology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 15, 2013
End Date
June 30, 2018
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Awards:

Physician-Scientist Strong Start Award. Duke School of Medicine.

Type
School
Awarded By
DUke School of Medicine
Date
January 01, 2017

Research Grant. Dermatology Foundation.

Type
National
Awarded By
Dermatology Foundation
Date
January 01, 2017

K08 Career Development Award. NIH/NIAMS.

Type
National
Awarded By
NIH/NIAMS
Date
January 01, 2013

AAI Young Investigator Presentation Award. American Association of Immunologists.

Type
National
Awarded By
American Association of Immunologists
Date
January 01, 2012

NIH training grant (T32) trainee. NIH.

Type
National
Awarded By
NIH
Date
January 01, 2011

Dermatology Research Fellowship Award. DFG and ADF (Arbeitsgemeinschaft Dermatologische Forschung, Society of Dermatological Research).

Type
National
Awarded By
DFG and ADF (Arbeitsgemeinschaft Dermatologische Forschung, Society of Dermatological Research)
Date
January 01, 2009

Albert Kligman Travel Fellowship Award. Society for Investigative Dermatology.

Type
National
Awarded By
Society for Investigative Dermatology
Date
January 01, 2006

Albert M. Kligman Travel Fellowship Award. Society for Investigative Dermatology.

Type
National
Awarded By
Society for Investigative Dermatology
Date
January 01, 2006

Postdoctoral Fellowship. DFG (Deutsche Forschungsgemeinschaft, German Research Foundation).

Type
National
Awarded By
DFG (Deutsche Forschungsgemeinschaft, German Research Foundation)
Date
January 01, 2006

Publications:

Shifting Paradigms in Allergic Contact Dermatitis: The Role of Innate Immunity.

The role of the innate immune system in allergic contact dermatitis (ACD) has traditionally been confined to the initial antigen sensitization phase. However, more recent findings have shown the role of innate immunity in additional aspects of ACD, including the effector phase of the classic type IV hypersensitivity reaction. As a result, the precise immunologic mechanisms mediating ACD are more complex than previously believed. The aim of this review is to provide insight into recent advances in understanding the role of the innate immune system in the pathogenesis of ACD, including novel mechanistic roles for macrophages, innate lymphoid cells, natural killer cells, innate γδ T cells, and other signaling molecules. These insights provide new opportunities for therapeutic intervention in ACD.

Authors
Brys, AK; Rodriguez-Homs, LG; Suwanpradid, J; Atwater, AR; MacLeod, AS
MLA Citation
Brys, Adam K., et al. “Shifting Paradigms in Allergic Contact Dermatitis: The Role of Innate Immunity..” J Invest Dermatol, May 2019. Pubmed, doi:10.1016/j.jid.2019.03.1133.
PMID
31101475
Source
pubmed
Published In
J Invest Dermatol
Publish Date
2019
DOI
10.1016/j.jid.2019.03.1133

Bad "Staph" in the Wound Environment of Diabetic Foot Ulcers.

Diabetic foot ulcers (DFUs) are a leading cause of high morbidity among diabetic patients. In this issue of Cell Host & Microbe, Kalan et al. (2019) examine the microbial bio-burden of DFUs and reveal biofilm and virulence pathways in the microbial metagenome that are linked to clinical healing outcomes.

Authors
MacLeod, AS
MLA Citation
MacLeod, Amanda S. “Bad "Staph" in the Wound Environment of Diabetic Foot Ulcers..” Cell Host Microbe, vol. 25, no. 5, May 2019, pp. 638–40. Pubmed, doi:10.1016/j.chom.2019.04.006.
PMID
31071293
Source
pubmed
Published In
Cell Host Microbe
Volume
25
Issue
5
Publish Date
2019
Start Page
638
End Page
640
DOI
10.1016/j.chom.2019.04.006

Inverted U-shaped relationship between vitamin D and ever-reported eczema in US adults.

BACKGROUND: Eczema is a skin condition which affects up to 10% to 20% of people worldwide. Previous literature finds that low vitamin D levels may be a risk factor for eczema, but the association is not clear. METHODS: We used the cross-sectional data from U.S. National Health and Nutrition Examination Survey 2005-2006. Adults were defined as 20 years and older. The association between eczema and serum 25-hydroxyvitamin D [25(OH)D] was estimated using multivariate logistic regression models adjusted for patient demographics, lifestyle variables, stress, and medical comorbidities. Restricted cubic spline analyses were performed to explore nonlinear relationship. We also stratified by race. RESULTS: A total of 3921 adults were included in the analysis. The prevalence of ever-report of eczema was 7.94% in US adults. Reports of eczema were higher in people with higher socioeconomic status, depressive symptoms, previous history of asthma and hay fever, female, sampled in summer, and nonHispanic white. The logistic regression found higher odds ratio of eczema in vitamin D deficiency group (<50 nmol/L) compared to sufficiency group (>75 nmol/L) (OR = 1.81, 95% CI: 1.09-3.01, P = 0.02). The spline analysis found an inverted U-shaped relationship between eczema and serum 25(OH)D level. Eczema risk reached the highest at around 45 nmol/L, with decreasing risk in both directions away from this value. This relationship was absent in nonHispanic black population. CONCLUSION: Vitamin D is associated with reports of eczema in nonHispanic white population, but not in the nonHispanic black population in the United States.

Authors
Wei, J; Jaleel, T; MacLeod, AS; Ji, JS
MLA Citation
Wei, Jia, et al. “Inverted U-shaped relationship between vitamin D and ever-reported eczema in US adults..” Allergy, vol. 74, no. 5, May 2019, pp. 964–75. Pubmed, doi:10.1111/all.13708.
PMID
30589434
Source
pubmed
Published In
Allergy
Volume
74
Issue
5
Publish Date
2019
Start Page
964
End Page
975
DOI
10.1111/all.13708

Innate antimicrobial immunity in the skin: A protective barrier against bacteria, viruses, and fungi.

Authors
Coates, M; Blanchard, S; MacLeod, AS
MLA Citation
Coates, Margaret, et al. “Innate antimicrobial immunity in the skin: A protective barrier against bacteria, viruses, and fungi..” Plos Pathog, vol. 14, no. 12, Dec. 2018. Pubmed, doi:10.1371/journal.ppat.1007353.
PMID
30522130
Source
pubmed
Published In
Plos Pathog
Volume
14
Issue
12
Publish Date
2018
Start Page
e1007353
DOI
10.1371/journal.ppat.1007353

Perivascular dendritic cells elicit anaphylaxis by relaying allergens to mast cells via microvesicles.

Anaphylactic reactions are triggered when allergens enter the blood circulation and activate immunoglobulin E (IgE)-sensitized mast cells (MCs), causing systemic discharge of prestored proinflammatory mediators. As MCs are extravascular, how they perceive circulating allergens remains a conundrum. Here, we describe the existence of a CD301b+ perivascular dendritic cell (DC) subset that continuously samples blood and relays antigens to neighboring MCs, which vigorously degranulate and trigger anaphylaxis. DC antigen transfer involves the active discharge of surface-associated antigens on 0.5- to 1.0-micrometer microvesicles (MVs) generated by vacuolar protein sorting 4 (VPS4). Antigen sharing by DCs is not limited to MCs, as neighboring DCs also acquire antigen-bearing MVs. This capacity of DCs to distribute antigen-bearing MVs to various immune cells in the perivascular space potentiates inflammatory and immune responses to blood-borne antigens.

Authors
Choi, HW; Suwanpradid, J; Kim, IH; Staats, HF; Haniffa, M; MacLeod, AS; Abraham, SN
MLA Citation
Choi, Hae Woong, et al. “Perivascular dendritic cells elicit anaphylaxis by relaying allergens to mast cells via microvesicles..” Science, vol. 362, no. 6415, Nov. 2018. Pubmed, doi:10.1126/science.aao0666.
PMID
30409859
Source
pubmed
Published In
Science
Volume
362
Issue
6415
Publish Date
2018
DOI
10.1126/science.aao0666

Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation.

The chemokine receptor CXCR3 plays a central role in inflammation by mediating effector/memory T cell migration in various diseases; however, drugs targeting CXCR3 and other chemokine receptors are largely ineffective in treating inflammation. Chemokines, the endogenous peptide ligands of chemokine receptors, can exhibit so-called biased agonism by selectively activating either G protein- or β-arrestin-mediated signaling after receptor binding. Biased agonists might be used as more targeted therapeutics to differentially regulate physiological responses, such as immune cell migration. To test whether CXCR3-mediated physiological responses could be segregated by G protein- and β-arrestin-mediated signaling, we identified and characterized small-molecule biased agonists of the receptor. In a mouse model of T cell-mediated allergic contact hypersensitivity (CHS), topical application of a β-arrestin-biased, but not a G protein-biased, agonist potentiated inflammation. T cell recruitment was increased by the β-arrestin-biased agonist, and biopsies of patients with allergic CHS demonstrated coexpression of CXCR3 and β-arrestin in T cells. In mouse and human T cells, the β-arrestin-biased agonist was the most efficient at stimulating chemotaxis. Analysis of phosphorylated proteins in human lymphocytes showed that β-arrestin-biased signaling activated the kinase Akt, which promoted T cell migration. This study demonstrates that biased agonists of CXCR3 produce distinct physiological effects, suggesting discrete roles for different endogenous CXCR3 ligands and providing evidence that biased signaling can affect the clinical utility of drugs targeting CXCR3 and other chemokine receptors.

Authors
Smith, JS; Nicholson, LT; Suwanpradid, J; Glenn, RA; Knape, NM; Alagesan, P; Gundry, JN; Wehrman, TS; Atwater, AR; Gunn, MD; MacLeod, AS; Rajagopal, S
MLA Citation
Smith, Jeffrey S., et al. “Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation..” Sci Signal, vol. 11, no. 555, Nov. 2018. Pubmed, doi:10.1126/scisignal.aaq1075.
PMID
30401786
Source
pubmed
Published In
Sci Signal
Volume
11
Issue
555
Publish Date
2018
DOI
10.1126/scisignal.aaq1075

A trichogenic tumor with aggressive features initially diagnosed as basal cell carcinoma.

Trichoblastic carcinoma is a rare carcinoma often arising in a pre-existing trichoblastoma. It may resemble basal cell carcinoma, posing a diagnostic challenge. Trichoblastic carcinoma is divided into low-grade and high-grade tumors. Low-grade tumors resemble basal cell carcinomas and are therefore synonymous in some classifications. High-grade tumors, which commonly present on the scalp in older individuals or in patients with Brooke-Spiegler syndrome, have been associated with a higher potential for distant metastasis and death. We present a case in which a 73-year-old female had a long-standing scalp nodule for over 30 years that rapidly increased in size. The patient's lesion was initially diagnosed as basal cell carcinoma on shave biopsy, but upon excision, revealed features concerning for trichoblastic carcinoma such as brisk mitotic activity and comedo-like necrosis. Sudden change in an atypical scalp lesion that has been present for many years should increase suspicion for an atypical trichogenic tumor, such as trichoblastic carcinoma.

Authors
Kwock, JT; Casady, M; Handfield, C; MacLeod, AS; Pavlis, MB
MLA Citation
Kwock, Jeffery T., et al. “A trichogenic tumor with aggressive features initially diagnosed as basal cell carcinoma..” Dermatol Online J, vol. 24, no. 9, Sept. 2018.
PMID
30677834
Source
pubmed
Published In
Dermatology Online Journal
Volume
24
Issue
9
Publish Date
2018

Neutrophils cause obstruction of eyelid sebaceous glands in inflammatory eye disease in mice.

Meibomian glands (MGs) are sebaceous glands of the eyelid margin that secrete lipids needed to avert tear evaporation and to help maintain ocular surface homeostasis. Obstruction of MGs or other forms of MG dysfunction can promote chronic diseases of the ocular surface. Although chronic eyelid inflammation, such as allergic eye disease, is an associated risk factor for obstructive MG dysfunction, it is not clear whether inflammatory processes contribute to the pathophysiology of MG obstruction. We show that polymorphonuclear neutrophils (PMNs) promoted MG obstruction in a chronic inflammatory model of allergic eye disease in mice. Analysis of leukocytes in tears of patients with MG dysfunction showed an increase in PMN numbers compared to healthy subjects. Moreover, PMN numbers in tears positively correlated with clinical severity of MG dysfunction. Our findings point to a role for PMNs in the pathogenesis and progression of MG dysfunction.

Authors
Reyes, NJ; Yu, C; Mathew, R; Kunnen, CM; Kalnitsky, J; Redfern, RL; Leonardi, A; Perez, VL; MacLeod, AS; Gupta, PK; Saban, DR
MLA Citation
Reyes, Nancy J., et al. “Neutrophils cause obstruction of eyelid sebaceous glands in inflammatory eye disease in mice..” Sci Transl Med, vol. 10, no. 451, July 2018. Pubmed, doi:10.1126/scitranslmed.aas9164.
PMID
30045980
Source
pubmed
Published In
Sci Transl Med
Volume
10
Issue
451
Publish Date
2018
DOI
10.1126/scitranslmed.aas9164

Association between vitamin D and eczema among adults in the US National Health and Nutrition Examination Survey

Authors
Wei, J; Jaleel, T; MacLeod, A; Ji, JS
MLA Citation
Wei, J., et al. “Association between vitamin D and eczema among adults in the US National Health and Nutrition Examination Survey.” Journal of Investigative Dermatology, vol. 138, no. 5, ELSEVIER SCIENCE INC, 2018, pp. S58–S58.
Source
wos
Published In
Journal of Investigative Dermatology
Volume
138
Issue
5
Publish Date
2018
Start Page
S58
End Page
S58

IL-27 signaling is relevant for IL-15 production and T cell cluster maintenance in allergic contact hypersensitivity

Authors
Suwanpradid, J; Hoang, P; Pontius, L; Kwock, J; MacLeod, A
MLA Citation
Suwanpradid, J., et al. “IL-27 signaling is relevant for IL-15 production and T cell cluster maintenance in allergic contact hypersensitivity.” Journal of Investigative Dermatology, vol. 138, no. 5, ELSEVIER SCIENCE INC, 2018, pp. S15–S15.
Source
wos
Published In
Journal of Investigative Dermatology
Volume
138
Issue
5
Publish Date
2018
Start Page
S15
End Page
S15

Innate antiviral immunity is activated upon skin injury via an IL-27/STAT1 axis

Authors
Kwock, J; Handfield, C; Suwanpradid, J; Hoang, P; Pontius, L; Maycock, J; MacLeod, A
MLA Citation
Kwock, J., et al. “Innate antiviral immunity is activated upon skin injury via an IL-27/STAT1 axis.” Journal of Investigative Dermatology, vol. 138, no. 5, ELSEVIER SCIENCE INC, 2018, pp. S157–S157.
Source
wos
Published In
Journal of Investigative Dermatology
Volume
138
Issue
5
Publish Date
2018
Start Page
S157
End Page
S157

Activation of nociceptive fibers following acute skin injury triggers innate antiviral immunity

Authors
Handfield, C; Kwock, J; Hoang, P; Suwanpradid, J; Han, Q; Ji, R; MacLeod, A
MLA Citation
Handfield, C., et al. “Activation of nociceptive fibers following acute skin injury triggers innate antiviral immunity.” Journal of Investigative Dermatology, vol. 138, no. 5, ELSEVIER SCIENCE INC, 2018, pp. S238–S238.
Source
wos
Published In
Journal of Investigative Dermatology
Volume
138
Issue
5
Publish Date
2018
Start Page
S238
End Page
S238

Stimulation of hair follicle stem cell proliferation through an IL-1 alpha dependent activation of gamma delta T-cells

Authors
Gund, R; Lee, P; Dutta, A; Pincha, N; Rana, I; Ghosh, S; Witherden, D; Kandyba, E; MacLeod, A; Kobielak, K; Havran, W; Jamora, C
MLA Citation
Gund, R., et al. “Stimulation of hair follicle stem cell proliferation through an IL-1 alpha dependent activation of gamma delta T-cells.” Journal of Investigative Dermatology, vol. 138, no. 5, 2018, pp. S229–S229.
Source
wos-lite
Published In
Journal of Investigative Dermatology
Volume
138
Issue
5
Publish Date
2018
Start Page
S229
End Page
S229

Innate Antiviral Immunity in the Skin.

Barrier sites such as the skin play a critical role in immune defense. They must maintain homeostasis with commensals and rapidly detect and limit pathogen invasion. This is accomplished in part through the production of endogenous antimicrobial peptides and proteins, which can be either constitutive or inducible. Here, we focus particularly on the control of innate antiviral proteins and present the basic aspects of their regulation in the skin by interferons (IFNs), IFN-independent immunity, and environmental factors. We also discuss the activity and (dys-)function of antiviral proteins in the context of skin-tropic viruses and highlight the relevance of the innate antiviral pathway as a potential therapeutic avenue for vulnerable patient populations and skin diseases with high risk for virus infections.

Authors
Handfield, C; Kwock, J; MacLeod, AS
MLA Citation
Handfield, Chelsea, et al. “Innate Antiviral Immunity in the Skin..” Trends Immunol, vol. 39, no. 4, Apr. 2018, pp. 328–40. Pubmed, doi:10.1016/j.it.2018.02.003.
PMID
29526487
Source
pubmed
Published In
Trends Immunol
Volume
39
Issue
4
Publish Date
2018
Start Page
328
End Page
340
DOI
10.1016/j.it.2018.02.003

Inflammation in Wound Repair: Role and Function of Inflammation in Wound Repair

© 2018 John Wiley & Sons, Inc. All rights reserved. Coordination of the innate immune and adaptive system during the inflammation stage is essential to successful wound healing. The process of acute wound healing can be divided into three phases: inflammation, proliferation, and remodeling. It is during the first phase, inflammation, that cells of the innate immune system generate an antimicrobial state and mount host defenses, resulting in the removal of pathogens and wound debris. Adaptive immune cells, in particular T cells, generate cytokines, which regulate expression of antimicrobial peptides and proteins and cutaneous immune cells relevant to wound healing. At the end of the inflammation phase, proinflammatory cells give way to anti-inflammatory cells, which leads to the resolution of inflammation and the initiation of repair during the proliferative phase. If proinflammatory signals are overt and resolution of inflammation is dysfunctional, non-healing wounds can develop.

Authors
Macleod, AS; Kwock, JT
MLA Citation
Macleod, A. S., and J. T. Kwock. “Inflammation in Wound Repair: Role and Function of Inflammation in Wound Repair.” Wound Healing: Stem Cells Repair and Restorations, Basic and Clinical Aspects, 2018, pp. 177–94. Scopus, doi:10.1002/9781119282518.ch14.
Source
scopus
Publish Date
2018
Start Page
177
End Page
194
DOI
10.1002/9781119282518.ch14

Stimulation of hair follicle stem cell proliferation through an IL-1 dependent activation of γδT-cells.

The cutaneous wound-healing program is a product of a complex interplay among diverse cell types within the skin. One fundamental process that is mediated by these reciprocal interactions is the mobilization of local stem cell pools to promote tissue regeneration and repair. Using the ablation of epidermal caspase-8 as a model of wound healing in Mus musculus, we analyzed the signaling components responsible for epithelial stem cell proliferation. We found that IL-1α and IL-7 secreted from keratinocytes work in tandem to expand the activated population of resident epidermal γδT-cells. A downstream effect of activated γδT-cells is the preferential proliferation of hair follicle stem cells. By contrast, IL-1α-dependent stimulation of dermal fibroblasts optimally stimulates epidermal stem cell proliferation. These findings provide new mechanistic insights into the regulation and function of epidermal cell-immune cell interactions and into how components that are classically associated with inflammation can differentially influence distinct stem cell niches within a tissue.

Authors
Lee, P; Gund, R; Dutta, A; Pincha, N; Rana, I; Ghosh, S; Witherden, D; Kandyba, E; MacLeod, A; Kobielak, K; Havran, WL; Jamora, C
MLA Citation
Lee, Pedro, et al. “Stimulation of hair follicle stem cell proliferation through an IL-1 dependent activation of γδT-cells..” Elife, vol. 6, Dec. 2017. Pubmed, doi:10.7554/eLife.28875.
PMID
29199946
Source
pubmed
Published In
Elife
Volume
6
Publish Date
2017
DOI
10.7554/eLife.28875

699 Evaluation of colorimetry and biomechanical properties in wounds of dermatologic patients with postoperative infection

Authors
Liu, J; Wolfe, S; Macleod, A; Powers, J
MLA Citation
Liu, J., et al. “699 Evaluation of colorimetry and biomechanical properties in wounds of dermatologic patients with postoperative infection.” Journal of Investigative Dermatology, vol. 137, no. 10, Elsevier BV, 2017, pp. S312–S312. Crossref, doi:10.1016/j.jid.2017.07.376.
Source
crossref
Published In
Journal of Investigative Dermatology
Volume
137
Issue
10
Publish Date
2017
Start Page
S312
End Page
S312
DOI
10.1016/j.jid.2017.07.376

Arginase1 Deficiency in Monocytes/Macrophages Upregulates Inducible Nitric Oxide Synthase To Promote Cutaneous Contact Hypersensitivity.

The innate immune components that modulate allergic contact hypersensitivity (CHS) responses are poorly defined. Using human skin from contact dermatitis patients and a mouse model of CHS, we find that hapten allergens disrupt the Arginase1 (Arg1) and inducible NO synthase (iNOS) dynamic in monocytes/macrophages (mono/MΦ), which renders those cells ineffectual in suppressing skin inflammation. Mice lacking Arg1 in MΦ develop increased CHS characterized by elevated ear thickening, mono/MΦ-dominated dermal inflammation, and increased iNOS and IL-6 expression compared with control mice. Treatment of Arg1flox/flox; LysMCre+/- mice with a selective NOS inhibitor or knockout of Nos2, encoding iNOS, significantly ameliorates CHS. Our findings suggest a critical role for Arg1 in mono/MΦ in suppressing CHS through dampening Nos2 expression. These results support that increasing Arg1 may be a potential therapeutic avenue in treating allergic contact dermatitis.

Authors
Suwanpradid, J; Shih, M; Pontius, L; Yang, B; Birukova, A; Guttman-Yassky, E; Corcoran, DL; Que, LG; Tighe, RM; MacLeod, AS
MLA Citation
Suwanpradid, Jutamas, et al. “Arginase1 Deficiency in Monocytes/Macrophages Upregulates Inducible Nitric Oxide Synthase To Promote Cutaneous Contact Hypersensitivity..” J Immunol, vol. 199, no. 5, 1 Sept. 2017, pp. 1827–34. Pubmed, doi:10.4049/jimmunol.1700739.
PMID
28747341
Source
pubmed
Published In
J Immunol
Volume
199
Issue
5
Publish Date
2017
Start Page
1827
End Page
1834
DOI
10.4049/jimmunol.1700739

IL-27 PROMOTES INNATE IMMUNITY AND ANTIVIRAL COMPETENCE IN WOUNDS

Authors
Kwock, J; Yang, B; Maycock, J; McFadden, M; Suwanpradid, J; Pontius, L; Hoang, P; Horner, S; Abraham, S; MacLeod, A
MLA Citation
Kwock, J., et al. “IL-27 PROMOTES INNATE IMMUNITY AND ANTIVIRAL COMPETENCE IN WOUNDS.” Wound Repair and Regeneration, vol. 25, no. 4, WILEY, 2017, pp. A20–21.
Source
wos
Published In
Wound Repair and Regeneration
Volume
25
Issue
4
Publish Date
2017
Start Page
A20
End Page
A21

IL-27 Facilitates Skin Wound Healing through Induction of Epidermal Proliferation and Host Defense.

Skin wound repair requires a coordinated program of epithelial cell proliferation and differentiation as well as resistance to invading microbes. However, the factors that trigger epithelial cell proliferation in this inflammatory process are incompletely understood. In this study, we demonstrate that IL-27 is rapidly and transiently produced by CD301b+ cells in the skin after injury. The functional role of IL-27 and CD301b+ cells is demonstrated by the finding that CD301b-depleted mice exhibit delayed wound closure in vivo, which could be rescued by topical IL-27 treatment. Furthermore, genetic ablation of the IL-27 receptor (Il27Ra-/-) attenuates wound healing, suggesting an essential role for IL-27 signaling in skin regeneration in vivo. Mechanistically, IL-27 feeds back on keratinocytes to stimulate cell proliferation and re-epithelialization in the skin, whereas IL-27 leads to suppression of keratinocyte terminal differentiation. Finally, we identify that IL-27 potently increases expression of the antiviral oligoadenylate synthetase 2, but does not affect expression of antibacterial human beta defensin 2 or regenerating islet-derived protein 3-alpha. Together, our data suggest a previously unrecognized role for IL-27 in regulating epithelial cell proliferation and antiviral host defense during the normal wound healing response.

Authors
Yang, B; Suwanpradid, J; Sanchez-Lagunes, R; Choi, HW; Hoang, P; Wang, D; Abraham, SN; MacLeod, AS
MLA Citation
Yang, Bin, et al. “IL-27 Facilitates Skin Wound Healing through Induction of Epidermal Proliferation and Host Defense..” J Invest Dermatol, vol. 137, no. 5, 2017, pp. 1166–75. Pubmed, doi:10.1016/j.jid.2017.01.010.
PMID
28132857
Source
pubmed
Published In
J Invest Dermatol
Volume
137
Issue
5
Publish Date
2017
Start Page
1166
End Page
1175
DOI
10.1016/j.jid.2017.01.010

IL-27 Facilitates Skin Wound Healing through Induction of Epidermal Proliferation and Host Defense

Authors
Yang, B; Suwanpradid, J; Sanchez-Lagunes, R; Choi, HW; Hoang, P; Wang, D; Abraham, SN; MacLeod, AS
MLA Citation
Yang, Bin, et al. “IL-27 Facilitates Skin Wound Healing through Induction of Epidermal Proliferation and Host Defense.” Journal of Investigative Dermatology, vol. 137, no. 5, May 2017, pp. 1166–75. Wos-lite, doi:10.1016/j.jid.2017.01.010.
Source
wos-lite
Published In
Journal of Investigative Dermatology
Volume
137
Issue
5
Publish Date
2017
Start Page
1166
End Page
1175
DOI
10.1016/j.jid.2017.01.010

576 IL-27 promotes skin wound repair through stimulation of keratinocyte proliferation and host immunity

Authors
Yang, B; Suwanpradid, J; Lagunes, RS; Choi, H; Hoang, P; Wang, D; Abraham, S; MacLeod, AS
MLA Citation
Yang, B., et al. “576 IL-27 promotes skin wound repair through stimulation of keratinocyte proliferation and host immunity.” Journal of Investigative Dermatology, vol. 137, no. 5, Elsevier BV, 2017, pp. S100–S100. Crossref, doi:10.1016/j.jid.2017.02.598.
Source
crossref
Published In
Journal of Investigative Dermatology
Volume
137
Issue
5
Publish Date
2017
Start Page
S100
End Page
S100
DOI
10.1016/j.jid.2017.02.598

678 Biased CXCR3 ligands differentially alter allergic contact hypersensitivity and chemotaxis

Authors
Smith, JS; Nicholson, L; Suwanpradid, J; Glenn, R; Gundry, J; Alagesan, P; Knape, N; Atwater, AR; Gunn, MD; MacLeod, AS; Lefkowitz, RJ; Rajagopal, S
MLA Citation
Smith, J. S., et al. “678 Biased CXCR3 ligands differentially alter allergic contact hypersensitivity and chemotaxis.” Journal of Investigative Dermatology, vol. 137, no. 5, Elsevier BV, 2017, pp. S117–S117. Crossref, doi:10.1016/j.jid.2017.02.701.
Source
crossref
Published In
Journal of Investigative Dermatology
Volume
137
Issue
5
Publish Date
2017
Start Page
S117
End Page
S117
DOI
10.1016/j.jid.2017.02.701

609 IL-27 signaling is essential for IL-15 production and mediates contact hypersensitivity

Authors
Pontius, L; Suwanpradid, J; Kwock, J; Yang, B; Maycock, J; Kedl, R; Hammer, G; MacLeod, AS
MLA Citation
Pontius, L., et al. “609 IL-27 signaling is essential for IL-15 production and mediates contact hypersensitivity.” Journal of Investigative Dermatology, vol. 137, no. 5, Elsevier BV, 2017, pp. S105–S105. Crossref, doi:10.1016/j.jid.2017.02.631.
Source
crossref
Published In
Journal of Investigative Dermatology
Volume
137
Issue
5
Publish Date
2017
Start Page
S105
End Page
S105
DOI
10.1016/j.jid.2017.02.631

573 Arginase1/Nos2 imbalance in macrophages mediates cutaneous contact hypersensitivity responses

Authors
Suwanpradid, J; Shih, M; Yang, B; Birukova, A; Guttman-Yassky, E; Que, L; Tighe, R; MacLeod, AS
MLA Citation
Suwanpradid, J., et al. “573 Arginase1/Nos2 imbalance in macrophages mediates cutaneous contact hypersensitivity responses.” Journal of Investigative Dermatology, vol. 137, no. 5, Elsevier BV, 2017, pp. S99–S99. Crossref, doi:10.1016/j.jid.2017.02.595.
Source
crossref
Published In
Journal of Investigative Dermatology
Volume
137
Issue
5
Publish Date
2017
Start Page
S99
End Page
S99
DOI
10.1016/j.jid.2017.02.595

594 IL-27 promotes innate antiviral competence in wounds

Authors
Kwock, J; Yang, B; Maycock, J; McFadden, M; Suwanpradid, J; Pontius, L; Hoang, P; Horner, S; MacLeod, AS
MLA Citation
Kwock, J., et al. “594 IL-27 promotes innate antiviral competence in wounds.” Journal of Investigative Dermatology, vol. 137, no. 5, Elsevier BV, 2017, pp. S103–S103. Crossref, doi:10.1016/j.jid.2017.02.616.
Source
crossref
Published In
Journal of Investigative Dermatology
Volume
137
Issue
5
Publish Date
2017
Start Page
S103
End Page
S103
DOI
10.1016/j.jid.2017.02.616

TRPV4 Moves toward Center-Fold in Rosacea Pathogenesis.

Mascarenhas et al. report that TRPV4 expression is upregulated in mast cells in response to the proteolytic cathelicidin fragment LL37 in a murine rosacea model and that TRPV4 loss of function attenuates mast cell degranulation. These findings render TRPV4 a translational-medical target in rosacea. However, signaling mechanisms causing increased expression of TRPV4 await elucidation. Moreover, we ask whether TRPV4-mediated Ca++-influx evokes mast cell degranulation.

Authors
Chen, Y; Moore, CD; Zhang, JY; Hall, RP; MacLeod, AS; Liedtke, W
MLA Citation
Chen, Yong, et al. “TRPV4 Moves toward Center-Fold in Rosacea Pathogenesis..” J Invest Dermatol, vol. 137, no. 4, Apr. 2017, pp. 801–04. Pubmed, doi:10.1016/j.jid.2016.12.013.
PMID
28340683
Source
pubmed
Published In
J Invest Dermatol
Volume
137
Issue
4
Publish Date
2017
Start Page
801
End Page
804
DOI
10.1016/j.jid.2016.12.013

Emerging Skin T-Cell Functions in Response to Environmental Insults.

Skin is the primary barrier between the body and the outside world, functioning not only as a physical barrier, but also as an immunologic first line of defense. A large number of T cells populate the skin. This review highlights the ability of these cutaneous T cells to regulate skin-specific environmental threats, including microbes, injuries, solar UV radiation, and allergens. Since much of this knowledge has been advanced from murine studies, we focus our review on how the mouse state has informed the human state, emphasizing the key parallels and differences.

Authors
Suwanpradid, J; Holcomb, ZE; MacLeod, AS
MLA Citation
Suwanpradid, Jutamas, et al. “Emerging Skin T-Cell Functions in Response to Environmental Insults..” J Invest Dermatol, vol. 137, no. 2, Feb. 2017, pp. 288–94. Pubmed, doi:10.1016/j.jid.2016.08.013.
PMID
27784595
Source
pubmed
Published In
J Invest Dermatol
Volume
137
Issue
2
Publish Date
2017
Start Page
288
End Page
294
DOI
10.1016/j.jid.2016.08.013

Arginase1/iNOS imbalance mediates cutaneous contact hypersensitivity responses

Authors
Suwanpradid, J; Shih, M; Yang, B; Birukova, A; Que, L; Tighe, R; MacLeod, AS
MLA Citation
Suwanpradid, J., et al. “Arginase1/iNOS imbalance mediates cutaneous contact hypersensitivity responses.” Experimental Dermatology, vol. 25, WILEY-BLACKWELL, 2016, pp. 26–26.
Source
wos
Published In
Experimental Dermatology
Volume
25
Publish Date
2016
Start Page
26
End Page
26

OX40+ Regulatory T Cells in Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell Responses and Associate with Metastatic Potential.

PURPOSE: Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumors continue to grow and persist. To investigate reasons for failure of T cells to mount a protective response in cSCC, we focused on regulatory T cells (Tregs) as this suppressive population is well represented among the infiltrating lymphocytes. EXPERIMENTAL DESIGN: Flow cytometry was conducted on cSCC lymphocytes and in vitro functional assays were performed using sorted tumoral T cells. Lymphocyte subsets in primary cSCCs were quantified immunohistochemically. RESULTS: FOXP3(+) Tregs were more frequent in cSCCs than in peripheral blood (P < 0.0001, n = 86 tumors). Tumoral Tregs suppressed proliferation of tumoral effector CD4(+) (P = 0.005, n = 10 tumors) and CD8(+) T cells (P = 0.043, n = 9 tumors) and inhibited IFNγ secretion by tumoral effector T cells (P = 0.0186, n = 11 tumors). The costimulatory molecule OX40 was expressed predominantly on tumoral Tregs (P < 0.0001, n = 15 tumors) and triggering OX40 with an agonist anti-OX40 antibody overcame the suppression exerted by Tregs, leading to increased tumoral effector CD4(+) lymphocyte proliferation (P = 0.0098, n = 10 tumors). Tregs and OX40(+) lymphocytes were more abundant in primary cSCCs that metastasized than in primary cSCCs that had not metastasized (n = 48 and n = 49 tumors, respectively). CONCLUSIONS: Tregs in cSCCs suppress effector T-cell responses and are associated with subsequent metastasis, suggesting a key role for Tregs in cSCC development and progression. OX40 agonism reversed the suppressive effects of Tregs in vitro, suggesting that targeting OX40 could benefit the subset of cSCC patients at high risk of metastasis. Clin Cancer Res; 22(16); 4236-48. ©2016 AACR.

Authors
Lai, C; August, S; Albibas, A; Behar, R; Cho, S-Y; Polak, ME; Theaker, J; MacLeod, AS; French, RR; Glennie, MJ; Al-Shamkhani, A; Healy, E
MLA Citation
Lai, Chester, et al. “OX40+ Regulatory T Cells in Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell Responses and Associate with Metastatic Potential..” Clin Cancer Res, vol. 22, no. 16, Aug. 2016, pp. 4236–48. Pubmed, doi:10.1158/1078-0432.CCR-15-2614.
PMID
27034329
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
22
Issue
16
Publish Date
2016
Start Page
4236
End Page
4248
DOI
10.1158/1078-0432.CCR-15-2614

LB811 Arginase1 in myeloid cells controls allergic contact hypersensitivity through tempering NOS2-associated inflammation

Authors
Suwanpradid, J; Shih, M; Phillips, T; Yang, B; Birukova, A; Que, L; Tighe, R; MacLeod, A
MLA Citation
Suwanpradid, J., et al. “LB811 Arginase1 in myeloid cells controls allergic contact hypersensitivity through tempering NOS2-associated inflammation.” Journal of Investigative Dermatology, vol. 136, no. 8, Elsevier BV, 2016, pp. B11–B11. Crossref, doi:10.1016/j.jid.2016.05.065.
Source
crossref
Published In
Journal of Investigative Dermatology
Volume
136
Issue
8
Publish Date
2016
Start Page
B11
End Page
B11
DOI
10.1016/j.jid.2016.05.065

Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch.

TRPV4 ion channels function in epidermal keratinocytes and in innervating sensory neurons; however, the contribution of the channel in either cell to neurosensory function remains to be elucidated. We recently reported TRPV4 as a critical component of the keratinocyte machinery that responds to ultraviolet B (UVB) and functions critically to convert the keratinocyte into a pain-generator cell after excess UVB exposure. One key mechanism in keratinocytes was increased expression and secretion of endothelin-1, which is also a known pruritogen. Here we address the question of whether TRPV4 in skin keratinocytes functions in itch, as a particular form of "forefront" signaling in non-neural cells. Our results support this novel concept based on attenuated scratching behavior in response to histaminergic (histamine, compound 48/80, endothelin-1), not non-histaminergic (chloroquine) pruritogens in Trpv4 keratinocyte-specific and inducible knock-out mice. We demonstrate that keratinocytes rely on TRPV4 for calcium influx in response to histaminergic pruritogens. TRPV4 activation in keratinocytes evokes phosphorylation of mitogen-activated protein kinase, ERK, for histaminergic pruritogens. This finding is relevant because we observed robust anti-pruritic effects with topical applications of selective inhibitors for TRPV4 and also for MEK, the kinase upstream of ERK, suggesting that calcium influx via TRPV4 in keratinocytes leads to ERK-phosphorylation, which in turn rapidly converts the keratinocyte into an organismal itch-generator cell. In support of this concept we found that scratching behavior, evoked by direct intradermal activation of TRPV4, was critically dependent on TRPV4 expression in keratinocytes. Thus, TRPV4 functions as a pruriceptor-TRP in skin keratinocytes in histaminergic itch, a novel basic concept with translational-medical relevance.

Authors
Chen, Y; Fang, Q; Wang, Z; Zhang, JY; MacLeod, AS; Hall, RP; Liedtke, WB
MLA Citation
Chen, Yong, et al. “Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch..” J Biol Chem, vol. 291, no. 19, May 2016, pp. 10252–62. Pubmed, doi:10.1074/jbc.M116.716464.
Website
http://hdl.handle.net/10161/12969
PMID
26961876
Source
pubmed
Published In
The Journal of Biological Chemistry
Volume
291
Issue
19
Publish Date
2016
Start Page
10252
End Page
10262
DOI
10.1074/jbc.M116.716464

The Innate Immune System in Acute and Chronic Wounds.

Significance: This review article provides an overview of the critical roles of the innate immune system to wound healing. It explores aspects of dysregulation of individual innate immune elements known to compromise wound repair and promote nonhealing wounds. Understanding the key mechanisms whereby wound healing fails will provide seed concepts for the development of new therapeutic approaches. Recent Advances: Our understanding of the complex interactions of the innate immune system in wound healing has significantly improved, particularly in our understanding of the role of antimicrobials and peptides and the nature of the switch from inflammatory to reparative processes. This takes place against an emerging understanding of the relationship between human cells and commensal bacteria in the skin. Critical Issues: It is well established and accepted that early local inflammatory mediators in the wound bed function as an immunological vehicle to facilitate immune cell infiltration and microbial clearance upon injury to the skin barrier. Both impaired and excessive innate immune responses can promote nonhealing wounds. It appears that the switch from the inflammatory to the proliferative phase is tightly regulated and mediated, at least in part, by a change in macrophages. Defining the factors that initiate the switch in such macrophage phenotypes and functions is the subject of multiple investigations. Future Directions: The review highlights processes that may be useful targets for further investigation, particularly the switch from M1 to M2 macrophages that appears to be critical as dysregulation of this switch occurs during defective wound healing.

Authors
MacLeod, AS; Mansbridge, JN
MLA Citation
MacLeod, Amanda S., and Jonathan N. Mansbridge. “The Innate Immune System in Acute and Chronic Wounds..” Adv Wound Care (New Rochelle), vol. 5, no. 2, Feb. 2016, pp. 65–78. Pubmed, doi:10.1089/wound.2014.0608.
Website
http://hdl.handle.net/10161/10102
PMID
26862464
Source
pubmed
Published In
Advances in Wound Care
Volume
5
Issue
2
Publish Date
2016
Start Page
65
End Page
78
DOI
10.1089/wound.2014.0608

ENTPD1 and PD-1/PD-1 ligands are highly expressed by skin-resident immune cells in subsets of human SCC

Authors
McCray, C; Cook, J; Streilein, R; Degan, S; Havran, W; Zhang, JY; MacLeod, AS
MLA Citation
McCray, C., et al. “ENTPD1 and PD-1/PD-1 ligands are highly expressed by skin-resident immune cells in subsets of human SCC.” Journal of Investigative Dermatology, vol. 135, NATURE PUBLISHING GROUP, 2015, pp. S7–S7.
Source
wos
Published In
Journal of Investigative Dermatology
Volume
135
Publish Date
2015
Start Page
S7
End Page
S7

Skin-resident T cells sense ultraviolet radiation-induced injury and contribute to DNA repair.

Skin-resident T cells have been shown to play important roles in tissue homeostasis and wound repair, but their role in UV radiation (UVR)-mediated skin injury and subsequent tissue regeneration is less clear. In this study, we demonstrate that acute UVR rapidly activates skin-resident T cells in humans and dendritic epidermal γδ T cells (DETCs) in mice through mechanisms involving the release of ATP from keratinocytes. Following UVR, extracellular ATP leads to an increase in CD69 expression, proliferation, and IL-17 production, and to changes in DETC morphology. Furthermore, we find that the purinergic receptor P2X7 and caspase-1 are necessary for UVR-induced IL-1 production in keratinocytes, which increases IL-17 secretion by DETCs. IL-17, in turn, induces epidermal TNF-related weak inducer of apoptosis and growth arrest and DNA damage-associated gene 45, two molecules linked to the DNA repair response. Finally, we demonstrate that DETCs and human skin-resident T cells limit DNA damage in keratinocytes. Taken together, our findings establish a novel role for skin-resident T cells in the UVR-associated DNA repair response and underscore the importance of skin-resident T cells to overall skin regeneration.

Authors
MacLeod, AS; Rudolph, R; Corriden, R; Ye, I; Garijo, O; Havran, WL
MLA Citation
MacLeod, Amanda S., et al. “Skin-resident T cells sense ultraviolet radiation-induced injury and contribute to DNA repair..” J Immunol, vol. 192, no. 12, June 2014, pp. 5695–702. Pubmed, doi:10.4049/jimmunol.1303297.
PMID
24808367
Source
pubmed
Published In
J Immunol
Volume
192
Issue
12
Publish Date
2014
Start Page
5695
End Page
5702
DOI
10.4049/jimmunol.1303297

Inforna

Authors
Velagapudi, PS; Gallo, SM; Disney, MD
MLA Citation
Velagapudi, P. S., et al. “Inforna.” Assay and Drug Development Technologies, vol. 12, no. 4, May 2014, pp. 201–02. Scopus, doi:10.1089/adt.2014.1204.lr.
Source
scopus
Published In
Assay and Drug Development Technologies
Volume
12
Issue
4
Publish Date
2014
Start Page
201
End Page
202
DOI
10.1089/adt.2014.1204.lr

IL-1β-dependent activation of dendritic epidermal T cells in contact hypersensitivity.

Substances that penetrate the skin surface can act as allergens and induce a T cell-mediated inflammatory skin disease called contact hypersensitivity (CHS). IL-17 is a key cytokine in CHS and was originally thought to be produced solely by CD4(+) T cells. However, it is now known that several cell types, including γδ T cells, can produce IL-17. In this study, we determine the role of γδ T cells, especially dendritic epidermal T cells (DETCs), in CHS. Using a well-established model for CHS in which 2,4-dinitrofluorobenzene (DNFB) is used as allergen, we found that γδ T cells are important players in CHS. Thus, more IL-17-producing DETCs appear in the skin following exposure to DNFB in wild-type mice, and DNFB-induced ear swelling is reduced by ∼50% in TCRδ(-/-) mice compared with wild-type mice. In accordance, DNFB-induced ear swelling was reduced by ∼50% in IL-17(-/-) mice. We show that DNFB triggers DETC activation and IL-1β production in the skin and that keratinocytes produce IL-1β when stimulated with DNFB. We find that DETCs activated in vitro by incubation with anti-CD3 and IL-1β produce IL-17. Importantly, we demonstrate that the IL-1R antagonist anakinra significantly reduces CHS responses, as measured by decreased ear swelling, inhibition of local DETC activation, and a reduction in the number of IL-17(+) γδ T cells and DETCs in the draining lymph nodes. Taken together, we show that DETCs become activated and produce IL-17 in an IL-1β-dependent manner during CHS, suggesting a key role for DETCs in CHS.

Authors
Nielsen, MM; Lovato, P; MacLeod, AS; Witherden, DA; Skov, L; Dyring-Andersen, B; Dabelsteen, S; Woetmann, A; Ødum, N; Havran, WL; Geisler, C; Bonefeld, CM
MLA Citation
Nielsen, Morten M., et al. “IL-1β-dependent activation of dendritic epidermal T cells in contact hypersensitivity..” J Immunol, vol. 192, no. 7, Apr. 2014, pp. 2975–83. Pubmed, doi:10.4049/jimmunol.1301689.
PMID
24600030
Source
pubmed
Published In
J Immunol
Volume
192
Issue
7
Publish Date
2014
Start Page
2975
End Page
2983
DOI
10.4049/jimmunol.1301689

A structurally distinct human mycoplasma protein that generically blocks antigen-antibody union

We report the discovery of a broadly reactive antibody-binding protein (Protein M) from human mycoplasma. The crystal structure of the ectodomain of transmembrane Protein M differs from other known protein structures, as does its mechanism of antibody binding. Protein M binds with high affinity to all types of human and nonhuman immunoglobulin G, predominantly through attachment to the conserved portions of the variable region of the k and l light chains. Protein M blocks antibody-antigen union, likely because of its large C-terminal domain extending over the antibody-combining site, blocking entry to large antigens. Similar to the other immunoglobulin-binding proteins such as Protein A, Protein M as well as its orthologs in other Mycoplasma species could become invaluable reagents in the antibody field.

Authors
Grover, RK; Zhu, X; Nieusma, T; Jones, T; Boero, I; MacLeod, AS; Mark, A; Niessen, S; Kim, HJ; Kong, L; Assad-Garcia, N; Kwon, K; Chesi, M; Smider, VV; Salomon, DR; Jelinek, DF; Kyle, RA; Pyles, RB; Glass, JI; Ward, AB; Wilson, IA; Lerner, RA
MLA Citation
Grover, R. K., et al. “A structurally distinct human mycoplasma protein that generically blocks antigen-antibody union.” Science, vol. 343, no. 6171, Jan. 2014, pp. 656–61. Scopus, doi:10.1126/science.1246135.
Source
scopus
Published In
Science (New York, N.Y.)
Volume
343
Issue
6171
Publish Date
2014
Start Page
656
End Page
661
DOI
10.1126/science.1246135

Dendritic epidermal T cells regulate skin antimicrobial barrier function.

The epidermis, the outer layer of the skin, forms a physical and antimicrobial shield to protect the body from environmental threats. Skin injury severely compromises the epidermal barrier and requires immediate repair. Dendritic epidermal T cells (DETC) reside in the murine epidermis where they sense skin injury and serve as regulators and orchestrators of immune responses. Here, we determined that TCR stimulation and skin injury induces IL-17A production by a subset of DETC. This subset of IL-17A-producing DETC was distinct from IFN-γ producers, despite similar surface marker profiles. Functionally, blocking IL-17A or genetic deletion of IL-17A resulted in delayed wound closure in animals. Skin organ cultures from Tcrd-/-, which lack DETC, and Il17a-/- mice both exhibited wound-healing defects. Wound healing was fully restored by the addition of WT DETC, but only partially restored by IL-17A-deficient DETC, demonstrating the importance of IL-17A to wound healing. Following skin injury, DETC-derived IL-17A induced expression of multiple host-defense molecules in epidermal keratinocytes to promote healing. Together, these data provide a mechanistic link between IL-17A production by DETC, host-defense, and wound-healing responses in the skin. These findings establish a critical and unique role of IL-17A-producing DETC in epidermal barrier function and wound healing.

Authors
MacLeod, AS; Hemmers, S; Garijo, O; Chabod, M; Mowen, K; Witherden, DA; Havran, WL
MLA Citation
MacLeod, Amanda S., et al. “Dendritic epidermal T cells regulate skin antimicrobial barrier function..” J Clin Invest, vol. 123, no. 10, Oct. 2013, pp. 4364–74. Pubmed, doi:10.1172/JCI70064.
PMID
24051381
Source
pubmed
Published In
J Clin Invest
Volume
123
Issue
10
Publish Date
2013
Start Page
4364
End Page
4374
DOI
10.1172/JCI70064

Activin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response.

Activin is an important orchestrator of wound repair, but its potential role in skin carcinogenesis has not been addressed. Here we show using different types of genetically modified mice that enhanced levels of activin in the skin promote skin tumour formation and their malignant progression through induction of a pro-tumourigenic microenvironment. This includes accumulation of tumour-promoting Langerhans cells and regulatory T cells in the epidermis. Furthermore, activin inhibits proliferation of tumour-suppressive epidermal γδ T cells, resulting in their progressive loss during tumour promotion. An increase in activin expression was also found in human cutaneous basal and squamous cell carcinomas when compared with control tissue. These findings highlight the parallels between wound healing and cancer, and suggest inhibition of activin action as a promising strategy for the treatment of cancers overexpressing this factor.

Authors
Antsiferova, M; Huber, M; Meyer, M; Piwko-Czuchra, A; Ramadan, T; MacLeod, AS; Havran, WL; Dummer, R; Hohl, D; Werner, S
MLA Citation
Antsiferova, Maria, et al. “Activin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response..” Nat Commun, vol. 2, Dec. 2011. Pubmed, doi:10.1038/ncomms1585.
PMID
22146395
Source
pubmed
Published In
Nature Communications
Volume
2
Publish Date
2011
Start Page
576
DOI
10.1038/ncomms1585

Functions of skin-resident γδ T cells.

The murine epidermis contains resident T cells that express a canonical γδ TCR and arise from fetal thymic precursors. These cells are termed dendritic epidermal T cells (DETC) and use a TCR that is restricted to the skin in adult animals. DETC produce low levels of cytokines and growth factors that contribute to epidermal homeostasis. Upon activation, DETC can secrete large amounts of inflammatory molecules which participate in the communication between DETC, neighboring keratinocytes and langerhans cells. Chemokines produced by DETC may recruit inflammatory cells to the epidermis. In addition, cell-cell mediated immune responses also appear important for epidermal-T cell communication. Information is provided which supports a crucial role for DETC in inflammation, wound healing, and tumor surveillance.

Authors
Macleod, AS; Havran, WL
MLA Citation
Macleod, Amanda S., and Wendy L. Havran. “Functions of skin-resident γδ T cells..” Cell Mol Life Sci, vol. 68, no. 14, July 2011, pp. 2399–408. Pubmed, doi:10.1007/s00018-011-0702-x.
PMID
21560071
Source
pubmed
Published In
Cell Mol Life Sci
Volume
68
Issue
14
Publish Date
2011
Start Page
2399
End Page
2408
DOI
10.1007/s00018-011-0702-x

Cutaneous infection by Mycobacterium haemophilum and kansasii in an IgA-deficient man.

BACKGROUND: The prevalence of infections by nontuberculous mycobacteria (NTM) has steadily increased over the past decades, especially in immunocompromised patients. CASE PRESENTATION: We present a patient with IgA-deficiency and mixed cutaneous infection by two slowly growing mycobacteria, Mycobacterium (M.) haemophilum and M. kansasii. CONCLUSIONS: Cutaneous M. haemophilum infections most often result from HIV or transplantation-associated immunosuppression. Rarely, M. haemophilum may also infect healthy patients or iatrogenically immunosuppressed patients without transplantation. M. kansasii is one of the most frequent NTM and large awareness exists about its involvement in human diseases. Mycobacterial diagnosis of cutaneous infections should be considered in long-lasting skin lesions.

Authors
Bekou, V; Büchau, A; Flaig, MJ; Ruzicka, T; Hogardt, M
MLA Citation
Bekou, Vassiliki, et al. “Cutaneous infection by Mycobacterium haemophilum and kansasii in an IgA-deficient man..” Bmc Dermatol, vol. 11, Jan. 2011. Pubmed, doi:10.1186/1471-5945-11-3.
PMID
21269422
Source
pubmed
Published In
Bmc Dermatology
Volume
11
Publish Date
2011
Start Page
3
DOI
10.1186/1471-5945-11-3

EGFR (trans)activation mediates IL-8 and distinct human antimicrobial peptide and protein production following skin injury.

Antimicrobial peptides and proteins (AMPs) are tools of the innate immune system employed at injury sites to protect the host from invading microbes and to promote wound repair. In this issue, Roupé et al. characterize epidermal innate immune responses induced by skin injury and the involvement of EGFR for distinct AMPs and IL-8 induction.

Authors
Büchau, AS
MLA Citation
Büchau, Amanda S. “EGFR (trans)activation mediates IL-8 and distinct human antimicrobial peptide and protein production following skin injury..” J Invest Dermatol, vol. 130, no. 4, Apr. 2010, pp. 929–32. Pubmed, doi:10.1038/jid.2009.371.
PMID
20231833
Source
pubmed
Published In
J Invest Dermatol
Volume
130
Issue
4
Publish Date
2010
Start Page
929
End Page
932
DOI
10.1038/jid.2009.371

The host defense peptide cathelicidin is required for NK cell-mediated suppression of tumor growth.

Tumor surveillance requires the interaction of multiple molecules and cells that participate in innate and the adaptive immunity. Cathelicidin was initially identified as an antimicrobial peptide, although it is now clear that it fulfills a variety of immune functions beyond microbial killing. Recent data have suggested contrasting roles for cathelicidin in tumor development. Because its role in tumor surveillance is not well understood, we investigated the requirement of cathelicidin in controlling transplantable tumors in mice. Cathelicidin was observed to be abundant in tumor-infiltrating NK1.1(+) cells in mice. The importance of this finding was demonstrated by the fact that cathelicidin knockout mice (Camp(-/-)) permitted faster tumor growth than wild type controls in two different xenograft tumor mouse models (B16.F10 and RMA-S). Functional in vitro analyses found that NK cells derived from Camp(-/-) versus wild type mice showed impaired cytotoxic activity toward tumor targets. These findings could not be solely attributed to an observed perforin deficiency in freshly isolated Camp(-/-) NK cells, because this deficiency could be partially restored by IL-2 treatment, whereas cytotoxic activity was still defective in IL-2-activated Camp(-/-) NK cells. Thus, we demonstrate a previously unrecognized role of cathelicidin in NK cell antitumor function.

Authors
Büchau, AS; Morizane, S; Trowbridge, J; Schauber, J; Kotol, P; Bui, JD; Gallo, RL
MLA Citation
Büchau, Amanda S., et al. “The host defense peptide cathelicidin is required for NK cell-mediated suppression of tumor growth..” J Immunol, vol. 184, no. 1, Jan. 2010, pp. 369–78. Pubmed, doi:10.4049/jimmunol.0902110.
PMID
19949065
Source
pubmed
Published In
J Immunol
Volume
184
Issue
1
Publish Date
2010
Start Page
369
End Page
378
DOI
10.4049/jimmunol.0902110

Bcl-3 acts as an innate immune modulator by controlling antimicrobial responses in keratinocytes.

Innate immune responses involve the production of antimicrobial peptides (AMPs), chemokines, and cytokines. We report here the identification of B-cell leukemia (Bcl)-3 as a modulator of innate immune signaling in keratinocytes. In this study, it is shown that Bcl-3 is inducible by the Th2 cytokines IL-4 and IL-13 and is overexpressed in lesional skin of atopic dermatitis (AD) patients. Bcl-3 was shown to be important to cutaneous innate immune responses as silencing of Bcl-3 by small-interfering RNA (siRNA) reversed the downregulatory effect of IL-4 on the HBD3 expression. Bcl-3 silencing enhanced vitamin D3 (1,25D3)-induced gene expression of cathelicidin AMP in keratinocytes, suggesting a negative regulatory function on cathelicidin transcription. Furthermore, 1,25D3 suppressed Bcl-3 expression in vitro and in vivo. This study identified Bcl-3 as an important modulator of cutaneous innate immune responses and its possible therapeutic role in AD.

Authors
Büchau, AS; MacLeod, DT; Morizane, S; Kotol, PF; Hata, T; Gallo, RL
MLA Citation
Büchau, Amanda S., et al. “Bcl-3 acts as an innate immune modulator by controlling antimicrobial responses in keratinocytes..” J Invest Dermatol, vol. 129, no. 9, Sept. 2009, pp. 2148–55. Pubmed, doi:10.1038/jid.2009.49.
PMID
19282837
Source
pubmed
Published In
J Invest Dermatol
Volume
129
Issue
9
Publish Date
2009
Start Page
2148
End Page
2155
DOI
10.1038/jid.2009.49

Vitamin D analogs differentially control antimicrobial peptide/"alarmin" expression in psoriasis.

Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory "alarmins" in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs beta-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IkappaB-alpha protein and inhibition of NF-kappaB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP "alarmin" expression might be a novel goal in treatment of chronic inflammatory skin diseases.

Authors
Peric, M; Koglin, S; Dombrowski, Y; Gross, K; Bradac, E; Büchau, A; Steinmeyer, A; Zügel, U; Ruzicka, T; Schauber, J
MLA Citation
Peric, Mark, et al. “Vitamin D analogs differentially control antimicrobial peptide/"alarmin" expression in psoriasis..” Plos One, vol. 4, no. 7, July 2009. Pubmed, doi:10.1371/journal.pone.0006340.
PMID
19623255
Source
pubmed
Published In
Plos One
Volume
4
Issue
7
Publish Date
2009
Start Page
e6340
DOI
10.1371/journal.pone.0006340

Pimecrolimus enhances TLR2/6-induced expression of antimicrobial peptides in keratinocytes.

Calcineurin inhibitors are potent inhibitors of T-cell-receptor mediated activation of the adaptive immune system. The effects of this class of drug on the innate immune response system are not known. Keratinocytes are essential to innate immunity in skin and rely on toll-like receptors (TLRs) and antimicrobial peptides to appropriately recognize and respond to injury or microbes. In this study we examined the response of cultured human keratinocytes to pimecrolimus. We observed that pimecrolimus enhances distinct expression of cathelicidin, CD14, and human beta-defensin-2 and beta-defensin-3 in response to TLR2/6 ligands. Some of these responses were further enhanced by 1,25 vitamin D3. Pimecrolimus also increased the functional capacity of keratinocytes to inhibit growth of Staphylococcus aureus and decreased TLR2/6-induced expression of IL-10 and IL-1beta. Furthermore, pimecrolimus inhibited nuclear translocation of NFAT and NF-kappaB in keratinocytes. These observations uncover a previously unreported function for pimecrolimus in cutaneous innate host defense.

Authors
Büchau, AS; Schauber, J; Hultsch, T; Stuetz, A; Gallo, RL
MLA Citation
Büchau, Amanda S., et al. “Pimecrolimus enhances TLR2/6-induced expression of antimicrobial peptides in keratinocytes..” J Invest Dermatol, vol. 128, no. 11, Nov. 2008, pp. 2646–54. Pubmed, doi:10.1038/jid.2008.135.
PMID
18496569
Source
pubmed
Published In
J Invest Dermatol
Volume
128
Issue
11
Publish Date
2008
Start Page
2646
End Page
2654
DOI
10.1038/jid.2008.135

Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D3.

Hormonally active vitamin D(3)-1,25-dihydroxyvitamin D(3) (1,25D3)-acts as a signaling molecule in cutaneous immunity by increasing pattern recognition through Toll-like receptor-2 (TLR2), and increasing the expression and function of antimicrobial peptides. Here we show that the actions of 1,25D3 on keratinocyte innate immune responses are influenced by histone acetylation and require the steroid receptor coactivator 3 (SRC3), which mediates inherent histone acetyltransferase (HAT) activity. SRC3 was detected in the suprabasal and granular layer of the skin, similar to cathelicidin expression. HAT activity was important to keratinocyte cathelicidin expression as the combination of histone deacetylase inhibitors (HDACi) (butyrate or trichostatin A) and 1,25D3 increased cathelicidin and CD14 expression and enhanced the antimicrobial function of keratinocytes against Staphylococcus aureus. This treatment, or activation of TLR2, also directly increased acetylation of histone 4. Small interfering RNA silencing of the vitamin D receptor or SRC3 blocked the induction of cathelicidin and CD14 by 1,25D3. HDACi could not reverse this effect or influence cathelicidin in the absence of 1,25D3, suggesting that both are necessary for function. These studies demonstrate that the epigenetic control of gene transcription by histone acetylation is important for 1,25D3-regulated antimicrobial and TLR function of keratinocytes, essential elements of the innate immune response of the skin.

Authors
Schauber, J; Oda, Y; Büchau, AS; Yun, Q-C; Steinmeyer, A; Zügel, U; Bikle, DD; Gallo, RL
MLA Citation
Schauber, Jürgen, et al. “Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D3..” J Invest Dermatol, vol. 128, no. 4, Apr. 2008, pp. 816–24. Pubmed, doi:10.1038/sj.jid.5701102.
PMID
17943182
Source
pubmed
Published In
J Invest Dermatol
Volume
128
Issue
4
Publish Date
2008
Start Page
816
End Page
824
DOI
10.1038/sj.jid.5701102

S100A15, an antimicrobial protein of the skin: regulation by E. coli through Toll-like receptor 4.

E. coli is a gram-negative bacterium rarely found on human skin. We investigated whether direct interaction of E. coli with keratinocytes might induce an innate immune response through recognition by pattern recognition receptors. The capacity of E. coli to activate innate immune responses and IL-8 induction was investigated. We found that E. coli significantly induced human S100A7 and S100A15 transcript abundance and IL-8 release in cultured primary human keratinocytes. S100A15 is a member of the S100 protein family with previously unknown function. E. coli induced effects could be inhibited by neutralizing Toll-like receptor 4 (TLR4) antibodies, suggesting that E. coli-induced IL-8 and S100A15 expression in human keratinocytes are TLR4 dependent. TLR4-/- mice lacked elevated mS100A15 expression after infection with E. coli in contrast to wild-type mice. In vitro, human S100A15 displayed antimicrobial activity against E. coli. Our findings suggest that E. coli modulates S100A15 and IL-8 expression of keratinocytes by recognition through TLR4.

Authors
Büchau, AS; Hassan, M; Kukova, G; Lewerenz, V; Kellermann, S; Würthner, JU; Wolf, R; Walz, M; Gallo, RL; Ruzicka, T
MLA Citation
Büchau, Amanda S., et al. “S100A15, an antimicrobial protein of the skin: regulation by E. coli through Toll-like receptor 4..” J Invest Dermatol, vol. 127, no. 11, Nov. 2007, pp. 2596–604. Pubmed, doi:10.1038/sj.jid.5700946.
PMID
17625598
Source
pubmed
Published In
J Invest Dermatol
Volume
127
Issue
11
Publish Date
2007
Start Page
2596
End Page
2604
DOI
10.1038/sj.jid.5700946

Innate immunity and antimicrobial defense systems in psoriasis.

Psoriasis is a chronic inflammatory disorder that is mediated by elements of the innate and adaptive immune systems. Its characteristic features in the skin consist of inflammatory changes in both dermis and epidermis, with abnormal keratinocyte differentiation and proliferation. Despite the elucidation of many aspects of psoriasis pathogenesis, some puzzling questions remain to be answered. A major question currently debated is whether psoriasis is a primary abnormality of the epidermal keratinocyte or a reflection of dysregulated bone marrow-derived immunocytes. In this review we will focus on understanding the role of the innate immune system in psoriasis and how this provides a rational solution to address the origin of this multifactorial disease. Innate immunity is nonspecific and genetically based. It protects the body against the constant risk of pathogens through the use of rapidly mobilized defenses that are able to recognize and kill a variety of threats (bacteria, fungi, viruses, etc). The key mechanisms of innate immune responses are the existence of receptors to recognize pathogens and the production of factors that kill pathogens, such as antimicrobial peptides and proteins. Any combination of excessive sensitivity of the innate detection system, or dysregulation of the response system, can manifest both an epidermal phenotype and an abnormal T-cell function. Thus, the multidimensional action of the innate immune system, its triggers, and its recently understood role in T-cell function argue for an important role for innate mechanisms of recognition and response in the pathogenesis of psoriasis.

Authors
Büchau, AS; Gallo, RL
MLA Citation
Büchau, Amanda S., and Richard L. Gallo. “Innate immunity and antimicrobial defense systems in psoriasis..” Clin Dermatol, vol. 25, no. 6, Nov. 2007, pp. 616–24. Pubmed, doi:10.1016/j.clindermatol.2007.08.016.
PMID
18021900
Source
pubmed
Published In
Clinics in Dermatology
Volume
25
Issue
6
Publish Date
2007
Start Page
616
End Page
624
DOI
10.1016/j.clindermatol.2007.08.016

Human S100A15 splice variants are differentially expressed in inflammatory skin diseases and regulated through Th1 cytokines and calcium.

The human calcium-binding protein (hS100A15) was first identified in inflamed hyperplastic psoriatic skin, where the S100A15 gene is transcribed into two mRNA splice variants, hS100A15-S and hS100A15-L. To compare the contribution of the human S100A15 (hS100A15) isoforms in skin inflammation and differentiation, we determined the expression, distribution and regulation of hS100A15-S and hS100A15-L in psoriasis and chronic atopic eczema compared with normal skin. We found that both hS100A15 transcripts were mainly distributed in the epidermis of normal and inflamed skin with hS100A15-L being the predominantly expressed mRNA isoform in both psoriasis and atopic eczema. In cultured keratinocytes, IL-1beta and Th1 cytokines significantly induced hS100A15-L compared with hS100A15-S. In contrast, Th2-derived cytokines had no influence on the expression of either hS100A15 splice variant. Differentiation of human keratinocytes induced by 1.2 mm calcium resulted in the upregulation of both hS100A15 mRNA isoforms. Our data show that both hS100A15 splice variants are differentially regulated and expressed with epidermal differentiation and skin inflammation. Overexpression of hS100A15 in chronic inflammatory skin diseases and regulation by inflammatory cytokines and calcium suggest that hS100A15 is involved in Th1-associated epithelial responses and epidermal maturation in normal and diseased human skin.

Authors
Wolf, R; Lewerenz, V; Büchau, AS; Walz, M; Ruzicka, T
MLA Citation
Wolf, Ronald, et al. “Human S100A15 splice variants are differentially expressed in inflammatory skin diseases and regulated through Th1 cytokines and calcium..” Exp Dermatol, vol. 16, no. 8, Aug. 2007, pp. 685–91. Pubmed, doi:10.1111/j.1600-0625.2007.00587.x.
PMID
17620096
Source
pubmed
Published In
Experimental Dermatology
Volume
16
Issue
8
Publish Date
2007
Start Page
685
End Page
691
DOI
10.1111/j.1600-0625.2007.00587.x

Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism.

An essential element of the innate immune response to injury is the capacity to recognize microbial invasion and stimulate production of antimicrobial peptides. We investigated how this process is controlled in the epidermis. Keratinocytes surrounding a wound increased expression of the genes coding for the microbial pattern recognition receptors CD14 and TLR2, complementing an increase in cathelicidin antimicrobial peptide expression. These genes were induced by 1,25(OH)2 vitamin D3 (1,25D3; its active form), suggesting a role for vitamin D3 in this process. How 1,25D3 could participate in the injury response was explained by findings that the levels of CYP27B1, which converts 25OH vitamin D3 (25D3) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-beta1. Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-beta1 from inducing cathelicidin, CD14, or TLR2 in human keratinocytes, while CYP27B1-deficient mice failed to increase CD14 expression following wounding. The functional consequence of these observations was confirmed by demonstrating that 1,25D3 enabled keratinocytes to recognize microbial components through TLR2 and respond by cathelicidin production. Thus, we demonstrate what we believe to be a previously unexpected role for vitamin D3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.

Authors
Schauber, J; Dorschner, RA; Coda, AB; Büchau, AS; Liu, PT; Kiken, D; Helfrich, YR; Kang, S; Elalieh, HZ; Steinmeyer, A; Zügel, U; Bikle, DD; Modlin, RL; Gallo, RL
MLA Citation
Schauber, Jürgen, et al. “Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism..” J Clin Invest, vol. 117, no. 3, Mar. 2007, pp. 803–11. Pubmed, doi:10.1172/JCI30142.
PMID
17290304
Source
pubmed
Published In
The Journal of Clinical Investigation
Volume
117
Issue
3
Publish Date
2007
Start Page
803
End Page
811
DOI
10.1172/JCI30142

Fever, episcleritis, epistaxis, and rash after safari holiday in Swaziland.

Authors
Büchau, AS; Wurthner, JU; Reifenberger, J; Ruzicka, T
MLA Citation
Büchau, Amanda Swantje, et al. “Fever, episcleritis, epistaxis, and rash after safari holiday in Swaziland..” Archives of Dermatology, vol. 142, no. 10, Oct. 2006, pp. 1365–66. Epmc, doi:10.1001/archderm.142.10.1365.
PMID
17043203
Source
epmc
Published In
Archives of Dermatology
Volume
142
Issue
10
Publish Date
2006
Start Page
1365
End Page
1366
DOI
10.1001/archderm.142.10.1365

[Inflammatory stage of incontinentia pigmenti (Bloch-Sulzberger syndrome)].

Authors
Kortüm, A-K; Büchau, AS; Assmann, B; Ruzicka, T; Bruch-Gerharz, D; Orth, U; Kruse, R
MLA Citation
Kortüm, A. .. K., et al. “[Inflammatory stage of incontinentia pigmenti (Bloch-Sulzberger syndrome)]..” Hautarzt, vol. 57, no. 4, Apr. 2006, pp. 330–31. Pubmed, doi:10.1007/s00105-006-1116-9.
PMID
16523270
Source
pubmed
Published In
Der Hautarzt; Zeitschrift Fur Dermatologie, Venerologie, Und Verwandte Gebiete
Volume
57
Issue
4
Publish Date
2006
Start Page
330
End Page
331
DOI
10.1007/s00105-006-1116-9

[Rickettsiosis subsequent to vacation in Swaziland].

Authors
Büchau, AS; Würthner, JU; Bylaite, M; Kukova, G; Ruzicka, T; Reifenberger, J
MLA Citation
Büchau, A. S., et al. “[Rickettsiosis subsequent to vacation in Swaziland]..” Hautarzt, vol. 57, no. 4, Apr. 2006, pp. 328–30. Pubmed, doi:10.1007/s00105-006-1114-y.
PMID
16523271
Source
pubmed
Published In
Der Hautarzt; Zeitschrift Fur Dermatologie, Venerologie, Und Verwandte Gebiete
Volume
57
Issue
4
Publish Date
2006
Start Page
328
End Page
330
DOI
10.1007/s00105-006-1114-y

[A severe course of bullous pemphigoid in a young man].

Authors
Eigelshoven, S; Bruch-Gerharz, D; Enderlein, E; Ruzicka, T; Büchau, AS; Hertl, M; Reifenberger, J; Schulte, K-W
MLA Citation
Eigelshoven, S., et al. “[A severe course of bullous pemphigoid in a young man]..” Hautarzt, vol. 57, no. 4, Apr. 2006, pp. 320–22. Pubmed, doi:10.1007/s00105-006-1110-2.
PMID
16523275
Source
pubmed
Published In
Der Hautarzt; Zeitschrift Fur Dermatologie, Venerologie, Und Verwandte Gebiete
Volume
57
Issue
4
Publish Date
2006
Start Page
320
End Page
322
DOI
10.1007/s00105-006-1110-2

[Reactive perforating collagenosis disease].

Authors
Büchau, AS; Lewerenz, V; Kruse, R; Neumann, NJ; Ruzicka, T; Reifenberger, J
MLA Citation
Büchau, A. S., et al. “[Reactive perforating collagenosis disease]..” Hautarzt, vol. 56, no. 10, Oct. 2005, pp. 963–65. Pubmed, doi:10.1007/s00105-005-1023-5.
PMID
16143875
Source
pubmed
Published In
Der Hautarzt; Zeitschrift Fur Dermatologie, Venerologie, Und Verwandte Gebiete
Volume
56
Issue
10
Publish Date
2005
Start Page
963
End Page
965
DOI
10.1007/s00105-005-1023-5

[Livedoid vasculopathy with heterozygous factor V Leiden mutation and sticky platelet syndrome].

A 64-year-old male patient presented with painful ulcerations and livedo racemosa of both lower limbs. He had a history of cerebral and myocardial infarctions. Dermatohistologic findings and laboratory tests of the patient's coagulation system revealed the diagnosis of livedoid vasculopathy with heterozygous factor V Leiden mutation and sticky platelet syndrome type II. Systemic treatment with acetylsalicylic acid and heparin as well as topical therapy with disinfectant and granulation-inducing agents resulted in improvement of the skin lesions.

Authors
Lewerenz, V; Burchardt, T; Büchau, A; Ruzicka, T; Megahed, M
MLA Citation
Lewerenz, V., et al. “[Livedoid vasculopathy with heterozygous factor V Leiden mutation and sticky platelet syndrome]..” Hautarzt, vol. 55, no. 4, Apr. 2004, pp. 379–81. Pubmed, doi:10.1007/s00105-004-0709-4.
PMID
15021932
Source
pubmed
Published In
Der Hautarzt; Zeitschrift Fur Dermatologie, Venerologie, Und Verwandte Gebiete
Volume
55
Issue
4
Publish Date
2004
Start Page
379
End Page
381
DOI
10.1007/s00105-004-0709-4

[IgA pemphigus. Successful treatment with mycophenolate mofetil].

IgA pemphigus is a rare intraepidermal autoimmune disease characterized by the presence of intercellular IgA deposits, intraepidermal acantholysis with infiltration of neutrophils, and circulating IgA autoantibodies against keratinocyte cell surface components. We report for the first time about a patient with IgA pemphigus who was successfully treated with mycophenolate mofetil.

Authors
Burchardt, T; Büchau, A; Ruzicka, T; Megahed, M
MLA Citation
Burchardt, T., et al. “[IgA pemphigus. Successful treatment with mycophenolate mofetil]..” Hautarzt, vol. 55, no. 4, Apr. 2004, pp. 387–89. Pubmed, doi:10.1007/s00105-004-0713-8.
PMID
15021936
Source
pubmed
Published In
Der Hautarzt; Zeitschrift Fur Dermatologie, Venerologie, Und Verwandte Gebiete
Volume
55
Issue
4
Publish Date
2004
Start Page
387
End Page
389
DOI
10.1007/s00105-004-0713-8

Generation of hydrogen peroxide and failure of antioxidative responses in pancreatic islets of male C57BL/6 mice are associated with diabetes induced by multiple low doses of streptozotocin.

AIMS/HYPOTHESIS: We studied the impact of the reactive oxygen species hydrogen peroxide (H2O2) and antioxidative enzymes on the pathogenesis of diabetes induced by multiple low doses of streptozotocin (MLD-STZ). METHODS: We isolated the islets of C57BL/6 mice. For ex vivo analyses, mice had been injected with MLD-STZ. For in vitro analyses, islets were incubated with different concentrations of STZ, with either of the two moieties of STZ, methylnitrosourea and D-glucose, with H2O2 or with alloxan. Levels of H2O2 generation were measured by the scopoletin method. We assessed mRNA expression of Cu/Zn and Mn superoxide dismutase, catalase, and glutathione peroxidase (GPX) by semiquantitative polymerase chain reaction. GPX activity was measured spectrophotometrically. In vitro, beta cell function was assayed by measuring basal and D-glucose-stimulated release of immunoreactive insulin using an ELISA kit. RESULTS: Ex vivo, MLD-STZ significantly increased H2O2 generation in male but not in female mice. It also increased GPX activity and mRNA expression of catalase, Cu/Zn and Mn superoxide dismutase, and GPX in female but not in male mice. In vitro, STZ significantly stimulated H2O2 generation in islets of male mice only. In male islets, alloxan increased H202 generation at a highly toxic concentration, but D-glucose and methylnitrosourea did not. Both STZ and H2O2 dose-dependently inhibited the release of immunoreactive insulin after a D-glucose challenge. CONCLUSIONS/INTERPRETATION: The results indicate that H2O2 participates in the pathogenesis of MLD-STZ diabetes in male C57BL/6 mice, which do not up-regulate antioxidative enzymes in islets. Conversely, female mice are protected, probably due to an increment of several enzymes with the potential to detoxify H2O2.

Authors
Friesen, NTE; Büchau, AS; Schott-Ohly, P; Lgssiar, A; Gleichmann, H
MLA Citation
Friesen, N. T. E., et al. “Generation of hydrogen peroxide and failure of antioxidative responses in pancreatic islets of male C57BL/6 mice are associated with diabetes induced by multiple low doses of streptozotocin..” Diabetologia, vol. 47, no. 4, Apr. 2004, pp. 676–85. Pubmed, doi:10.1007/s00125-004-1367-x.
PMID
15298345
Source
pubmed
Published In
Diabetologia
Volume
47
Issue
4
Publish Date
2004
Start Page
676
End Page
685
DOI
10.1007/s00125-004-1367-x

T Cells Expressing the Chemokine Receptor CXCR3 Localize to Positive Patch Test Reaction Sites.

Authors
Smith, JS; Suwanpradid, J; MacLeod, AS; Atwater, AR
MLA Citation
Smith, Jeffrey S., et al. “T Cells Expressing the Chemokine Receptor CXCR3 Localize to Positive Patch Test Reaction Sites..” Dermatitis, vol. 29, no. 4, pp. 228–29. Pubmed, doi:10.1097/DER.0000000000000367.
PMID
29698357
Source
pubmed
Published In
Dermatitis
Volume
29
Issue
4
Start Page
228
End Page
229
DOI
10.1097/DER.0000000000000367
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Research Areas:

  • Adenosine
  • Allergy
  • Antimicrobial Cationic Peptides
  • Cancer
  • Chemokines
  • Contact dermatitis
  • Cytokines
  • DNA Damage
  • Dendritic Cells
  • Immune Evasion
  • Immune recognition
  • Immune response
  • Immunity
  • Immunity, Innate
  • Immunologic Surveillance
  • Immunological tolerance
  • Immunosuppressive Agents
  • Immunotherapy
  • Infection
  • Inflammation
  • Keratinocytes
  • Macrophages
  • Psoriasis
  • Purinergic Agents
  • Skin
  • Skin Diseases
  • Translational Medical Research
  • Tumor Microenvironment
  • Ultraviolet microscopy
  • Ultraviolet radiation
  • Wound Healing