Department of Pathology
Asthma is a chronic inflammatory disease, which is associated with the recruitment of mast cells to the lung and their activation. It is well known that aggregation of high affinity IgE receptors (FceRI) on mast cells and the subsequent mediator release contributes to the development of allergic asthma. However, emerging evidence suggests that transactivation of G protein coupled receptors (GPCRs) for the complement component C3a contributes to the exacerbation of allergic diseases. The main focus of our laboratory has been to delineate how G protein coupled receptor kinases (GRKs) and the adaptor molecule β-arrestin regulate C3a receptor function in mast cells. We unexpectedly found that GRK2 and β-arrestin2 serve as novel adaptor proteins to promote IgE-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 FceRI signaling in mast cells to modulate allergic asthma.
Surface epithelial cells, when activated by pathogen-associated molecular patterns (PAMPs) release small cationic antibacterial peptides (AMPs), known as defensins and cathelicidins. These AMPs display potent antimicrobial activity, modulate immune responses and likely participate in the exacerbation of allergic diseases such as asthma and urticaria. Recently, we made the unexpected observation that AMPs activate human mast cells via a novel GPCR (Mas-related gene X2; MrgX2). Most interestingly, we found that unlike C3a receptor, MrgX2 is resistant to regulation by GRK2 or β-arrestin-2. It is noteworthy that unlike human mast cells, murine mast cells do not express MrgX2 and are resistant to activation by AMPs. We are currently engrafting human CD34+ hematopoietic stem cells (HSCs) into severely immune-deficient mice. In addition to human immune system, these “HUMANIZED MICE” develop human tissue mast cells are responsive to AMPs for activation in vivo. We are currently using the humanized mouse model to determine the role of MrgX2 and its signaling on anaphylaxis and asthma in vivo.