Raf kinase inhibitor protein negatively regulates FcεRI-mediated mast cell activation and allergic response

The signaling cascades triggered by the cross-linkage of immunoglobulin E (IgE) with its high-affinity receptor (FceRI) on mast cells contribute to multiple allergic disorders, such as asthma, rhinitis, and atopic dermatitis. Restraint of intracellular signals for mast cell activation is essential to restore homeostasis. In this study, we found that Raf kinase inhibitor protein (RKIP) negatively regulated mast cell activation. RKIP-deficient mast cells showed greater IgE-FceRI-mediated activation than wild-type mast cells. Consistently, RKIP deficiency in mast cells rendered mice more sensitive to IgE-FceRI-mediated allergic responses and ovalbumin-induced airway inflammation. Mechanistically, RKIP interacts with the p85 subunit of PI3K, prevents it from binding to GRB2-associated binding protein 2 (Gab2), and eventually inhibits the activation of the PI3K/Akt/NF-kappa B complex and its downstream signaling. Furthermore, the expression of RKIP was significantly downregulated in the peripheral blood of asthma patients and in the IgE-FceRI-stimulated mast cells. Collectively, our findings not only suggest that RKIP plays an important role in controlling mast cell-mediated allergic responses but also provide insight into therapeutic targets for mast cell-related allergic diseases.