SLAMF7 regulates goblet cell mucus production and negatively impacts gut homeostasis and commensalism

Crosstalk between the intestinal mucosal barrier and the gut microbiota contributes to maintaining intestinal homeostasis. Accumulating evidence suggests that diverse mechanisms are involved in maintaining intestinal homeostasis. Any disturbance in these pathways can compromise gut homeostasis and trigger chronic inflammatory diseases such as inflammatory bowel disease (IBD). However, how host factors regulate the intestinal mucosal barrier and change the gut microbiome has not been well defined. Here, we discovered that disruption of SLAMF7 protects against intestinal inflammation. SLAMF7 deficiency significantly altered the intestinal microbiota composition, specifically the expansion of the mucus-specific bacterium Akkermansia muciniphila. Moreover, SLAMF7 deficiency resulted in goblet cell generation by increasing the number of M2-like C1q+ macrophages, which may contribute to a thicker mucosal barrier. Mechanistically, SLAMF7 deficiency increased goblet cell generation through C1q+ M2-like macrophage polarization, which partly led to a thicker mucosal barrier. Depletion of SLAMF7 in intestinal macrophages upregulated C1q via activation of the STAT6-MafB pathway. The upregulation of C1q in macrophages resulted in a bias toward the M2 phenotype in response to damage-associated molecular patterns (DAMPs) stimulation. Accordingly, SLAMF7 activation induced a shift in macrophage polarization and reduced mucus secretion, which partially aggravated intestinal inflammation. Conversely, SLAMF7 knockdown mitigated DSS-induced intestinal inflammation to some extent. This work reveals the previously unrecognized functions of SLAMF7 in regulating intestinal inflammation and tissue homeostasis.