Amanda S MacLeod, MD
The MacLeod Lab investigates the dynamic regulation of innate immunity, with specific focus on host-microbial interactions, antimicrobial host defense, 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 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.
III. 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. One of such molecules is the ecto-ATPase CD39 which in tandem with CD73 hydrolyzes ATP into adenosine. 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.
IV. 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:
Her maiden name Büchau was used prior to MacLeod.
Education and Training
- M.D., Heinrich Heine University Düsseldorf (Germany), 2005
Selected Grants and Awards
- 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
- Immunotherapy to combat skin infections
- Targeting Immune Dysregulation in Psoriasis