Antagonistic Control of IgG-mediated Mast Cell Activation by Lyn and Fyn Kinases (86.8)

Abstract

Abstract Mast cells are key players of the innate immune system. In addition to their role in atopic disease, mast cell involvement is strongly suspected in inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and atherosclerosis. Once activated, they degranulate and produce cytokines, resulting in the recruitment of other immune cells. It is well-appreciated that mast cells are activated via the high-affinity immunoglobulin E (IgE) receptor FcϵRI. In this study we focus on mast cell activation via the immunoglobulin G (IgG) receptor FcγRII/RIII and downstream signaling by Fyn and Lyn kinases. Lyn-deficient mast cells displayed increased FcγR expression, correlating with enhanced IgG-mediated histamine and leukotriene C4 secretion. The mast cells did not show a change in IgG-mediated cytokine production, suggesting a restricted and negative regulatory role for Lyn kinase in mast cell IgG signaling. In contrast, we show that Fyn kinase is rapidly activated by IgG crosslinkage, and is required for both IgG-mediated histamine release and cytokine production in mast cells. We obtained similar results when studying Lyn- or Fyn-deficient basophils and macrophages. Finally, we found that Lyn-deficient mice had exacerbated responses to passive systemic anaphylactic shock elicited by IgG challenge in vivo. These data illustrate the importance of Src family kinases in IgG signaling, a means by which mast cells may be activated in chronic inflammatory diseases.