TGFbeta Promotes Mast Cell Effector Function By Targeting Bruton’s Tyrosine Kinase 3009

Abstract Description Mast cell (MC) activation via the IgE receptor, FcεRI, causes the release of mediators that are directly involved in the allergy diathesis. Patients with Loeys Dietz Syndrome (LDS), a disorder caused by loss-of-function variants in TGFβ receptor genes are highly predisposed to atopy, thus provide an opportunity to study the role of MC TGFβ signaling in allergy. We examined active and passive IgE responses in LDS mice and mice with conditional deletion of Tgfbr1 in MCs. Unexpectedly, both exhibited less IgE-mediated anaphylaxis and MC degranulation compared to WT controls. Mast cells differentiated from LDS patients or mice also exhibited reduced IgE-mediated degranulation compared to the respective controls. This could not be attributed to IgE or stem cell factor receptor expression on MCs, or to the distribution of MCs in tissues. Rather, it correlated with increased expression of dual specificity phosphatase 1 (DUSP1) and reduced phosphorylation of BTK. Chemical inhibition of DUSP1 in vivo resulted in a partial correction of anaphylaxis severity in LDS mice. In accord, DUSP1 specific siRNA corrected the LDS degranulation defect via correction of BTK phosphorylation. Therefore, decreased TGFbR signaling is associated with increased DUSP1 that alters FcεR1-induced proximal signaling. Taken together, TGFβ signaling promotes MC function by disrupting DUSP1-BTK mediated pathway, which likely contributes to the regulation of IgE-mediated MC functions and allergic responses. Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)