Amanda MacLeod

Overview:

The MacLeod Lab investigates the dynamic regulation of innate immunity, with specific focus on host-microbial interactions, antimicrobial host defense, antiviral proteins, and repair functions.

Skin is an active immune organ and comprises not only epithelial keratinocytes, but also harbors dendritic cells, macrophages, nerve cells, and other immune cells. Furthermore, the skin is inhabited by a multitude of microbes, including bacteria, viruses and fungi and even parasites. The healthy and controlled immune interactions of the skin barrier cells with microbes and environmental factors are critical to maintain homeostasis and to prevent overt immune responses resulting in disease. The dynamic regulation of innate host defense factors allows for critical protection against microbial pathogens in situations of barrier defects and injury.

We use interdisciplinary approaches, combining various disease mouse models, human skin tissues and cells, and techniques from immunology, stem cell biology, microbiology and pharmacology to ultimately reveal strategies that coordinate, regulate or co-opt innate immunity in the skin. This allows us to identify mechanisms that fundamentally control skin immunity and will help in the development of new immune-modulatory therapeutics and a better understanding of health and disease.

 

We study the interplay of innate  immune cells with microbial and additional environmental factors. Our interest is to decipher the mechanisms that facilitate antimicrobial immune surveillance and repair functions in the skin under homeostatic and challenged conditions.

I. Innate immune regulation and modulation during skin injury and microbial infection

Damage to the skin through physical injury and microbes initiates release of multiple pro-inflammatory cytokines and mediators including IL-27, 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 contamination 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. The focus of our laboratory is on identifying and characterizing such key factors that regulate innate  immunity in the skin. Fine regulation of the cutaneous innate immune response is critical to maintain skin barrier function and protection upon injury and infection.  Our studies on innate antimicrobial peptides and proteins (AMPs), including antiviral proteins, have fundamentally advanced our knowledge of how the innate immune system works in the skin.  We further aim to understand the dynamic regulation of innate antimicrobial host immunity during aging and in early life, in response to diverse microbial stimuli, and in various complex dermatological diseases, including eczema, psoriasis, hidradenitis suppurativa, wounds etc. Decoding the microbial-epithelial-immune dialogue in the skin  may offer insights into novel strategies of treatment.

 

II. Role of IL-27 in cutaneous immunity

IL-27, a member of the IL-12 family of heterodimeric cytokines, consists of p28 and Epstein-Barr virus gene 3 (EBI3) and signals through its receptor composed of IL-27RA and gp130. Previous studies indicated that IL-27 can play pro-inflammatory and anti-inflammatory roles depending on the cell type and context. In the context of infectious inflammation, a recent study reported that IL-27 is produced by CD103+ dermal dendritic cells (DC) in the skin , whereas other studies identified that IL-27 is produced by mesenteric lymph node CD103- DC, splenic CD4+ DC and macrophages. Our work identified IL-27 production in dermal CD301b+ monocyte-derived DC following injury. Here, IL-27 promotes the wound healing response by promoting keratinocyte proliferation. Furthermore, we have identified multiple new and unprecedented roles for IL-27 in cutaneous immunity in response to contact allergens, microbes and in psoriasis. Our lab recently described and published that IL-27 signaling provides a novel path of antiviral protein activation in the skin and that IL-27 signaling is critical in activating host defenses against cutaneous Zika virus infections.

 

III. Antiviral Proteins

A large part of our laboratory's efforts are  focused to better understanding the constitutive and inducible antiviral proteins and their mode of regulation in the skin. Antiviral proteins comprise Oligoadenylate Synthases (OAS), Protein Kinase R (PKR), Interferon-stimulated Gene (ISG) 15 and 20, and multiple Interferon Induced proteins with Tetratricopeptide repeats (IFIT) and Interferon-induced transmembrane proteins (IFITM) and others. Antiviral proteins provide a natural defense mechanism against viruses. Their expression and regulation in the skin are still poorly understood and our lab is providing some new and exciting insights into cutaneous innate antiviral immunity and the regulation of expression of antiviral proteins.


 

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.

Our lab website can be found here: https://sites.duke.edu/macleodlab/


Positions:

Adjunct Associate Professor in the Department of Dermatology

Dermatology
School of Medicine

Assistant Professor in the Department of Immunology

Immunology
School of Medicine

Adjunct Associate Professor in 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

Heinrich Heine University Düsseldorf (Germany)

Grants:

Immunotherapy to combat skin infections

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

IL-27 in skin host defense and regeneration

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Dynamic Control of Innate Antiviral Immunity in Skin Homeostasis and Inflammation

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Biasing CXCR3 Signaling to Modulate the Inflammatory Response

Administered By
Medicine, Cardiology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Immunomodulatory Biomaterials via Peptide and Protein Self-Assembly

Administered By
Biomedical Engineering
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Publications:

Multifactorial Design of a Supramolecular Peptide Anti-IL-17 Vaccine Toward the Treatment of Psoriasis.

Current treatments for chronic immune-mediated diseases such as psoriasis, rheumatoid arthritis, or Crohn's disease commonly rely on cytokine neutralization using monoclonal antibodies; however, such approaches have drawbacks. Frequent repeated dosing can lead to the formation of anti-drug antibodies and patient compliance issues, and it is difficult to identify a single antibody that is broadly efficacious across diverse patient populations. As an alternative to monoclonal antibody therapy, anti-cytokine immunization is a potential means for long-term therapeutic control of chronic inflammatory diseases. Here we report a supramolecular peptide-based approach for raising antibodies against IL-17 and demonstrate its efficacy in a murine model of psoriasis. B-cell epitopes from IL-17 were co-assembled with the universal T-cell epitope PADRE using the Q11 self-assembling peptide nanofiber system. These materials, with or without adjuvants, raised antibody responses against IL-17. Exploiting the modularity of the system, multifactorial experimental designs were used to select formulations maximizing titer and avidity. In a mouse model of psoriasis induced by imiquimod, unadjuvanted nanofibers had therapeutic efficacy, which could be enhanced with alum adjuvant but reversed with CpG adjuvant. Measurements of antibody subclass induced by adjuvanted and unadjuvanted formulations revealed strong correlations between therapeutic efficacy and titers of IgG1 (improved efficacy) or IgG2b (worsened efficacy). These findings have important implications for the development of anti-cytokine active immunotherapies and suggest that immune phenotype is an important metric for eliciting therapeutic anti-cytokine antibody responses.
Authors
Shores, LS; Kelly, SH; Hainline, KM; Suwanpradid, J; MacLeod, AS; Collier, JH
MLA Citation
Shores, Lucas S., et al. “Multifactorial Design of a Supramolecular Peptide Anti-IL-17 Vaccine Toward the Treatment of Psoriasis.Front Immunol, vol. 11, 2020, p. 1855. Pubmed, doi:10.3389/fimmu.2020.01855.
URI
https://scholars.duke.edu/individual/pub1459298
PMID
32973764
Source
pubmed
Published In
Frontiers in Immunology
Volume
11
Published Date
Start Page
1855
DOI
10.3389/fimmu.2020.01855

What causes hidradenitis suppurativa ?-15 years after.

The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30-April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote "Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy." (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as "the only inflammatory skin disease than can be healed". This anniversary article of 43 research-performing authors from all around the globe in the official journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future.
Authors
Zouboulis, CC; Benhadou, F; Byrd, AS; Chandran, NS; Giamarellos-Bourboulis, EJ; Fabbrocini, G; Frew, JW; Fujita, H; González-López, MA; Guillem, P; Gulliver, WPF; Hamzavi, I; Hayran, Y; Hórvath, B; Hüe, S; Hunger, RE; Ingram, JR; Jemec, GBE; Ju, Q; Kimball, AB; Kirby, JS; Konstantinou, MP; Lowes, MA; MacLeod, AS; Martorell, A; Marzano, AV; Matusiak, Ł; Nassif, A; Nikiphorou, E; Nikolakis, G; Nogueira da Costa, A; Okun, MM; Orenstein, LAV; Pascual, JC; Paus, R; Perin, B; Prens, EP; Röhn, TA; Szegedi, A; Szepietowski, JC; Tzellos, T; Wang, B; van der Zee, HH
MLA Citation
Zouboulis, Christos C., et al. “What causes hidradenitis suppurativa ?-15 years after.Exp Dermatol, vol. 29, no. 12, Dec. 2020, pp. 1154–70. Pubmed, doi:10.1111/exd.14214.
URI
https://scholars.duke.edu/individual/pub1463362
PMID
33058306
Source
pubmed
Published In
Exp Dermatol
Volume
29
Published Date
Start Page
1154
End Page
1170
DOI
10.1111/exd.14214

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton's tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.
Authors
Gudjonsson, JE; Tsoi, LC; Ma, F; Billi, AC; van Straalen, KR; Vossen, ARJV; van der Zee, HH; Harms, PW; Wasikowski, R; Yee, CM; Rizvi, SM; Xing, X; Xing, E; Plazyo, O; Zeng, C; Patrick, MT; Lowe, MM; Burney, RE; Kozlow, JH; Cherry-Bukowiec, JR; Jiang, Y; Kirma, J; Weidinger, S; Cushing, KC; Rosenblum, MD; Berthier, C; MacLeod, AS; Voorhees, JJ; Wen, F; Kahlenberg, JM; Maverakis, E; Modlin, RL; Prens, EP
MLA Citation
Gudjonsson, Johann E., et al. “Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.Jci Insight, vol. 5, no. 19, Oct. 2020. Pubmed, doi:10.1172/jci.insight.139930.
URI
https://scholars.duke.edu/individual/pub1457280
PMID
32853177
Source
pubmed
Published In
Jci Insight
Volume
5
Published Date
DOI
10.1172/jci.insight.139930

The sweat gland antimicrobial peptide dermcidin is downregulated in hidradenitis suppurativa and non-healing skin wounds but upregulated in healing-wounds

Authors
Mariottoni, PRCGB; Coates, M; Corcoran, D; Kirshner, HF; Jaleel, T; Brown, DA; MacLeod, AS
MLA Citation
Mariottoni, P. Rosa Coutinho Goulart Borges, et al. “The sweat gland antimicrobial peptide dermcidin is downregulated in hidradenitis suppurativa and non-healing skin wounds but upregulated in healing-wounds.” Journal of Investigative Dermatology, vol. 140, no. 7, 2020, pp. S40–S40.
URI
https://scholars.duke.edu/individual/pub1456381
Source
wos-lite
Published In
Journal of Investigative Dermatology
Volume
140
Published Date
Start Page
S40
End Page
S40

Circadian factors BMAL1 and CLOCK control transcriptional innate antiviral immunity programs in response to skin wounding

Authors
Kirchner, S; Lei, V; Coates, M; Handfield, C; Corcoran, D; Ling, X; Shannon, J; Mariottoni, PRCGB; Hughes, D; Waters, D; Dzirasa, K; MacLeod, AS
MLA Citation
Kirchner, S., et al. “Circadian factors BMAL1 and CLOCK control transcriptional innate antiviral immunity programs in response to skin wounding.” Journal of Investigative Dermatology, vol. 140, no. 7, 2020, pp. S107–S107.
URI
https://scholars.duke.edu/individual/pub1456571
Source
wos-lite
Published In
Journal of Investigative Dermatology
Volume
140
Published Date
Start Page
S107
End Page
S107

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