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

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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.

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