MyD88-mediated signaling in intestinal fibroblasts regulates macrophage antimicrobial defense and prevents dysbiosis in the gut.

Fibroblasts that reside in the gut mucosa are among the key regulators of innate immune cells, but their role in the regulation of the defense functions of macrophages remains unknown. MyD88 is suggested to shape fibroblast responses in the intestinal microenvironment. We found that mice lacking MyD88 in fibroblasts showed a decrease in the colonic antimicrobial defense, developing dysbiosis and aggravated dextran sulfate sodium (DSS)-induced colitis. These pathological changes were associated with the accumulation of Arginase 1 macrophages with low antimicrobial defense capability. Mechanistically, the production of interleukin (IL)-6 and CCL2 downstream of MyD88 was critically involved in fibroblast-mediated support of macrophage antimicrobial function, and IL-6/CCL2 neutralization resulted in the generation of macrophages with decreased production of the antimicrobial peptide cathelicidin and impaired bacterial clearance. Collectively, these findings revealed a critical role of fibroblast-intrinsic MyD88 signaling in regulating macrophage antimicrobial defense under colonic homeostasis, and its disruption results in dysbiosis, predisposing the host to the development of intestinal inflammation.