Immune balance of the gastrointestinal tract is orchestrated by heterogenous subsets of innate immune cells. In a previous study, we revealed that gut-resident CD169+ macrophages are involved in exacerbation of DSS-induced colitis in mice. In response to mucosal injury, they produce a chemokine CCL8/MCP-2, which was responsible for the recruitment of inflammatory monocytes. These findings suggested that CD169+ macrophages are attractive targets for the suppression of mucosal injury, however, a genetic program that determines the phenotype of these macrophages remained obscure.
In this study, we identified a transcription factor c-Maf that is highly expressed in the colon and lymph node CD169+ macrophages. By analyzing c-Maf-deficient chimeric mice, we found that c-Maf is dispensable for the development or localization of CD169+ macrophages in the colon, but is essential for expressing acute inflammatory response genes such as CCL8. To our surprise, c-Maf not only promoted acute inflammatory responses but also suppressed some of the downstream targets of Nrf2, a master regulator for oxidative stress responses. When CD169+ macrophages were exposed to stimuli derived from bacterial components, they produced acute inflammatory response genes in c-Maf-dependent manner, and simultaneously downregulated c-Maf. This downregulation of c-Maf was attributable to accelerated degradation through proteasome pathway and miR-129-mediated mRNA silencing. The c-Maf repression induced the Nrf2-dominant cytoprotective phenotype in the same macrophages, represented by upregulation of SLPI and xCT.
Collectively, our study indicate that gut macrophages shift from pro-inflammatory to cytoprotective phenotype by changing c-Maf expression level during inflammation.