CCR6-CCL20 signaling modulates immunoglobulin isotype switching at the mucosal barrier during gut inflammation

Abstract

Abstract Chemokine CCL20, secreted by gut epithelial cells, demonstrates markedly increased expression during episodes of chronic inflammation and infection. Mucosal barriers recruit more CCR6+ B cells and have higher immunogloblin A (IgA) Ab levels during normal, infectious, and inflammatory states. Ig isotypes at the mucosal surface are pivotal in modulating inflammatory responses and controlling infections. However, the intrinsic signaling pathway mediated by CCR6-CCL20 in B cells—in particular, its impact on Ig isotype expression—remains insufficiently investigated. In this study, the dextran sodium sulfate (DSS)–induced gut inflammation model in C57BL/6 mice was used. Our findings indicate that DSS administration elevates CCL20 production in the gut epithelium, which, in turn, enhances the differentiation of IgA+ B cells in gut-associated lymphoid tissues, while concurrently reducing both IgG1+ B-cell populations and serum IgG1 levels, in a CCR6-dependent manner. Furthermore, stimulation with CCL20 through CCR6 induces phosphorylation of the AKT/mTOR/STAT3 signaling pathways in B cells. Pharmacological inhibition of mTOR signaling with rapamycin effectively abrogated CCL20-driven differentiation of IgA+ B cells. Collectively, these results suggest a significant role for CCR6-CCL20 signaling, alongside other costimulatory mechanisms, in regulating Ig isotype switching at the mucosal barrier during intestinal inflammation, thereby offering important insights into CCR6-mediated inflammatory pathologies.