Zouboulis, Christos C., Farida Benhadou, Angel S. Byrd, Nisha S. Chandran, Evangelos J. Giamarellos-Bourboulis, Gabriella Fabbrocini, John W. Frew, et al. “What causes hidradenitis suppurativa ?-15 years after.” Exp Dermatol 29, no. 12 (December 2020): 1154–70. https://doi.org/10.1111/exd.14214.
Amanda S MacLeod, MD
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:
Her maiden name Büchau was used prior to MacLeod.
Our lab website can be found here: https://sites.duke.edu/macleodlab/
Education and Training
- M.D., Heinrich Heine University Düsseldorf (Germany), 2005
Selected Grants and Awards
- Basic Immunology Training Program
- Dynamic Control of Innate Antiviral Immunity in Skin Homeostasis and Inflammation
- Biasing CXCR3 Signaling to Modulate the Inflammatory Response
- Medical Scientist Training Program
- Immunomodulatory Biomaterials via Peptide and Protein Self-Assembly
- Training Program in Developmental and Stem Cell Biology
- Molecular Mycology and Pathogenesis Training Program
- Immunotherapy to combat skin infections
- Targeting Immune Dysregulation in Psoriasis
- IL-27 in skin host defense and regeneration
- Role of IL-27 signaling in cutaneous regeneration and host defense
- ATP in Skin Immunity
Gudjonsson, Johann E., Lam C. Tsoi, Feiyang Ma, Allison C. Billi, K. R. van Straalen, A. R. J. V. Vossen, H. H. van der Zee, et al. “Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.” Jci Insight 5, no. 19 (October 2, 2020). https://doi.org/10.1172/jci.insight.139930.
Sil, Payel, Jutamas Suwanpradid, Ginger Muse, Artiom Gruzdev, Liwen Liu, David L. Corcoran, Cynthia J. Willson, et al. “Noncanonical autophagy in dermal dendritic cells mediates immunosuppressive effects of UV exposure.” J Allergy Clin Immunol 145, no. 5 (May 2020): 1389–1405. https://doi.org/10.1016/j.jaci.2019.11.041.
Kwock, Jeffery T., Chelsea Handfield, Jutamas Suwanpradid, Peter Hoang, Michael J. McFadden, Kevin F. Labagnara, Lauren Floyd, et al. “IL-27 signaling activates skin cells to induce innate antiviral proteins and protects against Zika virus infection.” Sci Adv 6, no. 14 (April 2020): eaay3245. https://doi.org/10.1126/sciadv.aay3245.
Shores, Lucas S., Sean H. Kelly, Kelly M. Hainline, Jutamas Suwanpradid, Amanda S. MacLeod, and Joel H. Collier. “Multifactorial Design of a Supramolecular Peptide Anti-IL-17 Vaccine Toward the Treatment of Psoriasis.” Front Immunol 11 (2020): 1855. https://doi.org/10.3389/fimmu.2020.01855.
Handfield, Chelsea, Jeffery Kwock, Peter Hoang, and Amanda S. MacLeod. “Activation of nociceptive fibers following skin injury triggers antiviral host defense immunity.” In Journal of the American Academy of Dermatology, 81:AB15–AB15. MOSBY-ELSEVIER, 2019.
Whitley, M., C. Lai, J. Suwanpradid, C. Reid, R. Rudolph, D. Zelac, W. L. Havran, et al. “494 UV-induced CD39 expression promotes epidermal DNA damage and development of cutaneous squamous cell carcinoma.” In Journal of Investigative Dermatology, 139:S299–S299. Elsevier BV, 2019. https://doi.org/10.1016/j.jid.2019.07.544.
Whitley, M., C. Lai, J. Suwanpradid, C. Reid, R. Rudolph, D. Zelac, W. Havran, et al. “Ultraviolet radiation induces ENTPD1 expression, which inhibits epidermal DNA damage repair via interleukin-27 and promotes cutaneous squamous cell carcinoma development.” In British Journal of Dermatology, 180:E194–95. WILEY, 2019.
Handfield, C., J. Kwock, P. Hoang, and A. S. MacLeod. “Activation of Trpv1(+) nociceptive fibers stimulates an innate antiviral immune response following skin injury.” In Journal of Investigative Dermatology, 139:S114–S114. ELSEVIER SCIENCE INC, 2019.
Kirchner, S., X. Ling, M. Coates, J. Shannon, P Rosa Coutinho Goulart Mariottoni, A. S. MacLeod, and D. Corcoran. “Cutaneous antiviral protein expression is regulated by the circadian clock.” In Journal of Investigative Dermatology, 139:S82–S82. ELSEVIER SCIENCE INC, 2019.
Coates, M., D. Corcoran, P Rosa Coutinho Goulart Mariottoni, T. Jaleel, D. Brown, J. Murray, M. Morasso, and A. S. MacLeod. “The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature that has distinct overlap with wounded skin.” In Journal of Investigative Dermatology, 139:S162–S162. ELSEVIER SCIENCE INC, 2019.
Whitley, M. J., C. Lai, J. Suwanpradid, R. R. Rudolph, D. Zelac, W. Havran, J. Cook, et al. “UV-induced CD39 expression on immunosuppressive memory T cells in human cutaneous squamous cell carcinoma.” In Journal of Investigative Dermatology, 139:S128–S128. ELSEVIER SCIENCE INC, 2019.