Mast cells in host defense and chronic inflammatory diseases
Mast cells are granulated cells of hematopoietic lineage that reside close to blood vessels primarily at sites exposed to the external environment, such as the skin, oral/gastrointestinal mucosa and respiratory tract. They contribute to vascular homeostasis, innate/adaptive immunity and wound healing. Mast cells are, however, best known for their roles in allergic and inflammatory diseases such as anaphylaxis, food allergy, rhinitis, itch, urticaria, periodontitis, atopic dermatitis and asthma. Mast cells express a newly discovered G protein coupled receptor (GPCR) known as Mas-related G protein coupled receptor X2 (MRGPRX2) and the high affinity IgE receptor (Fc-epsilonRI). As the only mast cell lab at Penn, we are interested in delineating how MRGPRX2 and Fc-epsilonRI contribute to host defense and allergic/inflammatory diseases.
MRGPRX2: Activation of surface epithelial cells by pathogen-associated molecular patterns (PAMPs) results in the generation of host defense antimicrobial peptides (HDPs). These HDPs display potent antimicrobial activity and modulate immune responses via the activation of mast cells through MRGPRX2. In addition to its immunomodulatory function, MRGPRX2 likely participates in pseudo-allergic drug reactions and chronic inflammatory diseases such as urticaria, periodontitis and asthma exacerbation. A unique feature of MRGPRX2 that distinguishes it from other GPCRs is that it is activated by multiple cationic ligands including HDPs, neuropeptides (substance P and hemokinin-1), eosinophil major basic protein (MBP), eosinophil peroxidase (EPO), the neutrophil-derived cathelicidin LL-37 and many FDA approved peptidergic drugs. We are currently using cellular, molecular and imaging approaches to delineate the mechanisms involved in the regulation of MRGPRX2 in vitro and humanized mice to study its function in vivo.
Fc-epsilonRI: Aggregation of Fc-epsilonRI on mast cells by antigen and the release of proinflammatory mediators contribute to the pathogenesis of anaphylaxis and allergic asthma. It is well documented that GPCR kinases (GRKs) and the adapter protein β-arrestin contribute to the desensitization of most GPCRs. We recently made the unexpected observation that GRK2 and β-arrestin2 regulate Fc-epsilonRI-mediated mast cell chemotaxis, degranulation and cytokine gene expression. We are currently utilizing both in vitro and in vivo approaches to delineate how GRK2 and β-arrestin2 regulate Fc-epsilonRI signaling in mast cells to modulate anaphylaxis and allergic asthma.
Current lab members:
Saptarshi Roy, Ph.D. (Postdoctoral Researcher)
Ibrahim Alkanfari DDS (DScD student)
Chalatip Chompunud Na Ayudhya DDS (DScD student)
Manorak, Wichayapha DDS (MSOB student)
Tahsin Jahan M.S. (Research Specialist)
Anirban Ganguly B.S. (Research Specialist)
Projects are available for interested undergraduate, dental and graduate students to study mast cell MRGPRX2 and Fc-epsilonRI