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MacLeod Laboratory

Welcome to Amanda MacLeod's lab homepage.  Our lab is in the Department of Dermatology and is located in the School of Medicine at Duke University.
 
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Research Interests:

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.

 

Publications  (Please note Dr. MacLeod's maiden name is Büchau.)
  • 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. A Structurally Distinct Human Mycoplasma Protein that Generically Blocks Antigen-Antibody Union. Science. 2014;343:656-661.

  • MacLeod, AS; Rudolph, R; Corriden, R; Ye, I; Garijo, O; Havran, WL. Skin-resident T cells sense ultraviolet radiation-induced injury and contribute to DNA repair. Journal of Immunology. 2014;192:5695-5702.

  • Nielsen, NM; Lovato, P; MacLeod, AS; Witherden, DA; Skov, L; Dyring-Anderson, B; Dabelsteen, S; Woetmann, A; Odum, N; Havran, WL; Geisler, C; Bonefeld, CM. IL-1ß-dependent activation of dendritic epidermal T cells in contact hypersensitivity. Journal of Immunology. 2014;192:2975-2983.

  • MacLeod, AS; Hemmers, S; Garijo, O; Chabod, M; Mowen, K; Witherden, DA; Havran, WL. Dendritic epidermal T cells regulate skin antimicrobial barrier function. Journal of Clinical Investigation. 2013;123:4364-4374.

  • Antsiferova, M; Huber, M; Meyer, M; Piwko-Czuchra, A; Ramadan, T; MacLeod, AS; Havran, WL; Dummer, R; Hohl, D; Werner, S. Activin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response. Nature Communications. 2011;2:576-576.

  • Bekou, V; Büchau, A; Flaig, MJ; Ruzicka, T; Hogardt, M. Cutaneous infection by Mycobacterium haemophilum and kansasii in an IgA-deficient man. BMC Dermatology. 2011;11:3-3.

  • MacLeod, AS; Havran, WL. Functions of skin-resident gamma deltaT cells. Cellular and Molecular Life Sciences. 2011;68:2399-2408.

  • Büchau, AS. EGFR (Trans)activation Mediates IL-8 and Distinct Human Antimicrobial Peptide and Protein Production following Skin Injury. Journal of Investigative Dermatology. 2010;130:929-932.

  • Büchau, AS; Morizane, S; Trowbridge, J; Schauber, J; Kotol, P; Bui, JD; Gallo, RL. The host defense peptide cathelicidin is required for NK cell-mediated suppression of tumor growth. Journal of Immunology. 2010;184:369-378.

  • Büchau, AS; MacLeod, DT; Morizane, S; Kotol, PF; Hata, T; Gallo, RL. Bcl-3 Acts as an Innate Immune Modulator by Controlling Antimicrobial Responses in Keratinocytes. Journal of Investigative Dermatology. 2009;129:2148-2155.

  • Peric, M; Koglin, S; Dombrowski, Y; Groß, K; Bradac, E; Büchau, A; Steinmeyer, A; Zügel, U; Ruzicka, T; Schauber, J. Vitamin D Analogs Differentially Control Antimicrobial Peptide/"Alarmin"Expression in Psoriasis. PLoS One. 2009;4:e6340-e6340.

  • Büchau, AS; Schauber, J; Hultsch, T; Stuetz, A; Gallo, RL. Pimecrolimus Enhances TLR2/6-Induced Expression of Antimicrobial Peptides in Keratinocytes. Journal of Investigative Dermatology. 2008;128:2646-2654.

  • Schauber, J; Oda, Y; Büchau, AS; Yun, Q-C; Steinmeyer, A; Zügel, U; Bikle, DD; Gallo, RL. Histone Acetylation in Keratinocytes Enables Control of the Expression of Cathelicidin and CD14 by 1,25-Dihydroxyvitamin D3. Journal of Investigative Dermatology. 2008;128:816-824.

  • Büchau, AS; Gallo, RL. Innate immunity and antimicrobial defense systems in psoriasis. Clinics in Dermatology. 2007;25:616-624.

  • Büchau, AS; Hassan, M; Kukova, G; Lewerenz, V; Kellermann, S; Würthner, JU; Wolf, R; Walz, M; Gallo, RL; Ruzicka, T. S100A15, an Antimicrobial Protein of the Skin: Regulation by E. coli through Toll-Like Receptor 4. Journal of Investigative Dermatology. 2007;127:2596-2604.

  • 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. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. Journal of Clinical Investigation. 2007;117:803-811.

  • Wolf, R; Lewerenz, V; Büchau, AS; Walz, M; Ruzicka, T. Human S100A15 splice variants are differentially expressed in inflammatory skin diseases and regulated through Th1 cytokines and calcium. Experimental Dermatology. 2007;16:685-691.

  • Büchau, AS. Fever, Episcleritis, Epistaxis, and Rash After Safari Holiday in Swaziland. Archives of Dermatology. 2006;142:1361-1361.

  • Büchau, AS; Würthner, JU; Bylaite, M; Kukova, G; Ruzicka, T; Reifenberger, J. Rickettsiose nach Urlaub in Swaziland. Der Hautarzt: Zeitschrift fuer Dermatologie, Allergologie, Venerologie und verwandte Gebiete. 2006;57:328-330.

  • Eigelshoven, S; Bruch-Gerharz, D; Enderlein, E; Ruzicka, T; Büchau, AS; Hertl, M; Reifenberger, J; Schulte, K-W. Schwerer Verlauf eines bullösen Pemphigoids bei einem jungen Mann. Der Hautarzt: Zeitschrift fuer Dermatologie, Allergologie, Venerologie und verwandte Gebiete. 2006;57:320-322.

  • Kortüm, A-K; Büchau, AS; Assmann, B; Ruzicka, T; Bruch-Gerharz, D; Orth, U; Kruse, R. Entzündliches Stadium der Incontinentia pigmenti (Bloch-Sulzberger-Syndrom). Der Hautarzt: Zeitschrift fuer Dermatologie, Allergologie, Venerologie und verwandte Gebiete. 2006;57:330-331.

  • Büchau, AS; Lewerenz, V; Kruse, R; Neumann, NJ; Ruzicka, T; Reifenberger, J. Reaktive perforierende Kollagenose. Der Hautarzt: Zeitschrift fuer Dermatologie, Allergologie, Venerologie und verwandte Gebiete. 2005;56:963-965.

  • Burchardt, T; Büchau, A; Ruzicka, T; Megahed, M. IgA-Pemphigus. Der Hautarzt: Zeitschrift fuer Dermatologie, Allergologie, Venerologie und verwandte Gebiete. 2004;55:387-389.

  • Büchau, AS; Schott-Ohly, P; Lgssiar, A; Gleichmann, H; Friesen, NTE. 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. 2004;47:676-685.

  • Lewerenz, V; Burchardt, T; Büchau, A; Ruzicka, T; Megahed, M. Livedovaskulopathie bei heterozygoter Faktor-V-Leiden-Mutation und Sticky-Platelet-Syndrom. Der Hautarzt: Zeitschrift fuer Dermatologie, Allergologie, Venerologie und verwandte Gebiete. 2004;55:379-381.