Lyn/Fyn-STAT5 cascade in IgG-mediated inflammation

Abstract The Src family kinases Lyn and Fyn provide critical and antagonistic controls over mast cell responses to IgE and IgG mediated activation. Similarly, Fyn activates, while Lyn impedes IgE-induced STAT5 phosphorylation, which is critical for IgE-activated cytokine production. However, the role of STAT5B, the paralog that selectively influences cytokine production downstream of IgE, remains uncovered in the context of IgG-induced responses. Therefore, we examined the importance of STAT5 in IgG signaling, and broadened these studies to test the role for Lyn, Fyn, and Stat5 in IgG-mediated inflammation in vivo. Consistent with IgE, STAT5B KO mast cells produced significantly less cytokines and chemokines after IgG-induced activation in vitro. On the other hand, IgG-induced cytokine production in STAT5B KO macrophages was unaffected, indicating that the non-redundant role of STAT5B might be lineage-restricted. To expand these studies, we employed the K/BxN model of inflammatory arthritis, in which macrophages do play a critical role. In this model, Fyn or STAT5B deficiency did not alter arthritic inflammation. By contrast, Lyn deficiency significantly exacerbated arthritis. These studies indicate clinically relevant, lineage-restricted role for the Lyn/Fyn-STAT5 cascade, showing that inhibitory effects of Lyn kinase are critical in macrophage-driven inflammatory responses.