Sirtuin 6 is a negative regulator of FcεRI signaling and anaphylactic responses

Abstract

Background: Binding IgE to a cognate allergen causes aggregation of Fc epsilon receptor I (Fc epsilon RI) in mast cells, resulting in activation of receptor-associated Src family tyrosine kinases, including Lyn and Syk. Protein tyrosine phosphatase, receptor type C (PTPRC), also known as CD45, has emerged as a positive regulator of Fc epsilon RI signaling by dephosphorylation of the inhibitory tyrosine of Lyn. Objective: Sirtuin 6 (Sirt6), a NAD(+)-dependent deacetylase, exhibits an anti-inflammatory property. It remains to be determined, however, whether Sirt6 attenuates mast cell-associated diseases, including anaphylaxis. Methods: Fc epsilon RI signaling and mast cell degranulation were measured after IgE cross-linking in murine bone marrow-derived mast cells (BMMCs) and human cord blood-derived mast cells. To investigate the function of Sirt6 in mast cell activation in vivo, we used mast cell-dependent animal models of passive systemic anaphylaxis (PSA) and passive cutaneous anaphylaxis (PCA). Results: Sirt6-deficient BMMCs augmented IgE-Fc epsilon RI-mediated signaling and degranulation compared to wild-type BMMCs. Reconstitution of mast cell-deficient Kit(w-sh/W-sh) mice with BMMCs received from Sirt6 knockout mice developed more severe PSA and PCA compared to mice engrafted with wild-type BMMCs. Similarly, genetic overexpression or pharmacologic activation of Sirt6 suppressed mast cell degranulation and blunted responses to PCA. Mechanistically, Sirt6 deficiency increased PTPRC transcription via acetylating histone H3, leading to enhanced aggregation of Fc epsilon RI in BMMCs. Finally, we recapitulated the Sirt6 regulation of PTPRC and Fc epsilon RI signaling in human mast cells. Conclusions: Sirt6 acts as a negative regulator of Fc epsilon RI signaling cascade in mast cells by suppressing PTPRC transcription. Activation of Sirt6 may therefore represent a promising and novel therapeutic strategy for anaphylaxis.