The YAP/TEAD4 transcriptional complex in intestinal macrophages promotes M2 polarization and alleviates DSS-induced colitis via the regulation of C/EBPβ

Suppressing inflammation and promoting intestinal epithelial regeneration are the keys to mucosal healing in individuals with ulcerative colitis (UC). The upregulation of epithelial YAP and the induction of macrophages to polarize to the M2 phenotype in the mucosa can promote intestinal epithelial regeneration and alleviate ulcerative colitis. However, the role of YAP in macrophage polarization remains unclear. Here, we explored the effects of YAP on macrophage polarization and its biological role in a mouse DSS-induced colitis model. The results showed that YAP upregulation in macrophages could induce M2 polarization and increase the levels of anti-inflammatory cytokines such as IL-10 and IL-13. In addition, when mice were infused with YAP-overexpressing and empty vector-transfected macrophages, compared with control mice, YAP-overexpressing mice presented slower weight loss, a longer colon length, less intestinal inflammation, and a better arrangement of crypts. Moreover, macrophages in the lamina propria of the mouse colonic mucosa presented mainly the M2 phenotype in YAP-overexpressing macrophage-infused DSS-treated mice. Mechanistically, knockdown of the expression of the transcription factor TEAD4 in YAP-overexpressing macrophages inhibited macrophage M2 polarization and decreased anti-inflammatory cytokine expression, accompanied by the downregulated expression of C/EBPβ. Furthermore, silencing C/EBPβ following YAP overexpression suppressed M2 polarization. Chromatin immunoprecipitation revealed that TEAD4 was enriched at the C/EBPβ promoter region in YAP-overexpressing macrophages. Thus, YAP in macrophages regulates C/EBPβ expression through the transcription factor TEAD4, which mediates macrophage M2 polarization and inhibits the expression of inflammatory cytokines, thereby exerting inhibitory effects on intestinal inflammation and promoting mucosal healing in a colitis model.