Department of Pathology
Cross-linking of high affinity IgE receptors (FcRI) on mast cells by antigen leads to the release of inflammatory mediators, which cause the symptoms associated with allergic diseases. Emerging evidence suggests that G protein coupled receptors (GPCRs) expressed on mast cells play a critical role in modulating allergic diseases. Our studies are focused on GPCRs for the complement component C3a. Specifically, we are interested in determining how C3a receptor phosphorylation and the recruitment of adapter molecules (β-arrestin and PSD-95/Dlg/Zo1 (PDZ) domain proteins) regulate allergic responses. We are utilizing cellular, biochemical and proteomic approaches to determine the role of G protein coupled receptor kinases (GRKs) on C3a receptor phosphorylation and modulation of mast cell function. Biochemical, proteomic and live cell imaging studies are being performed to determine how β-arrestin and PDZ domain proteins regulate C3a receptor signaling. We are also using a number of murine models to determine how mast cell-specific modulation of C3a receptor and its signaling components regulate allergic responses in vivo.
Another focus of our research is to delineate the role of epithelial cell-mast cell interaction on the pathogenesis of allergic diseases. These studies are based on the recent finding that a newly identified epithelial cell-derived cytokine IL-33, which activates a previously known orphan receptor ST2, and synergizes with antigen/IgE for Th2 cytokine generation in mast cells. We are testing the novel idea that the adapter molecule MyD88 is critical for the synergy between IL-33 and IgE for Th2 cytokine generation and allergic inflammation. For these studies, we are retrovirally transducing bone marrow progenitor cells with genetically modified MyD88 and differentiating these cells into mast cells ex vivo. Our goal is to identify the motifs on MyD88 that regulates the synergy between IL-33 and IgE in mast cells. We are also adoptively transferring mast cells expressing genetically modified MyD88 into mast cell-deficient mice to determine how mast cell-specific modulation of MyD88 regulates allergic inflammation in vivo.
Students participating in the School’s student research program can work on the folllowing projects:
Project #1: Microbial infection, Epithelial cells, Human β-defensins, and mast cells in innate immunity: Mast cells are found in all vascularized tissues in close proximity to surface epithelia in the skin, lung and oral mucosa and play an important role in innate immunity. Following microbial infection, human β-defensins (HBDs) are produced by epithelial cells, which are thought to protect the host by direct killing of microbes. We hypothesize that HBDs also activate a new family of G protein coupled receptors known as Mas-related genes (MrgX) in human mast cells. This results in substantial release of mast cell proteases, which facilitates microbial killing. The goal of this project is (a) to determine how the functions of MrgX receptors are regulated in human mast cells in vitro and (b) to assess their role in host defense in vivo.
Project #2: Mast cells, Human α-defensins, neutrophils in innate immunity and inflammation: Effects of mast cells in innate immunity require the recruitment and activation of neutrophils. Antimicrobial peptides α-defensins, which are secreted from human neutrophil granules (HND; human neutrophil defensins) not only promote microbial killing, but also cause mast cell mediator release. We hypothesize that HNDs activate one or more of the four MrgX receptors (MrgX1 – MrgX4) expressed in mast cells to amplify the innate immune response. The goal of this project is to determine how HNDs and MrgX receptors co-ordinate neutrophil and mast cell interaction in host defense and inflammatory diseases.
Project #3: Epithelial cell-derived cytokine interleukin-33 (IL-33) and mast cells in allergic asthma. Aggregation of high affinity IgE receptors (FcεRI) on mast cells by allergen results in rapid histamine release and the generation of lipid-derived mediators, which cause symptoms associated with allergic diseases such as rhinitis and asthma. IL-33 produced by epithelial cells exacerbates allergic responses but the mechanism of action is unknown. We propose that IL-33 and its receptor ST2 synergizes with allergen/FcεRI to promote enhanced mast cells mediator release, resulting in exaggerated allergic response. Studies are performed with human mast cells in vitro and mast cell-deficient mice in vivo.
Project #4: Complement component C3a and mast cells in allergic asthma. The complement system plays a central role in innate immunity but also mediates a variety of inflammatory diseases including allergic asthma. We have shown that human mast cells express G protein coupled receptors for C3a (C3aR). Our goal in this project is to determine how protein kinases and adapter molecules regulate C3aR signaling in human mast cells in vitro and allergic asthma in vivo.