MTDH promotes intestinal inflammation by positively regulating TLR signaling.

Macrophages in the intestinal mucosa can rapidly engage Toll-like receptor (TLR)-mediated inflammatory responses to defect against pathogen invasion, but these same innate immune responses can also drive the induction of colitis. Our previous research revealed that metadherin (MTDH), is overexpressed in multiple cancers and plays vital roles in tumor progression. However, the role of MTDH in intestinal inflammation is largely unknown. In this study, we found the MTDH expression in colonic lamina propria (CLP) macrophages was positively correlated with inflammatory colitis severity. MTDH -/- mice were protected against the symptoms of DSS-induced colitis, however, adoptive transfer of MTDH wild-type (WT) monocytes partially restored the susceptibility of MTDH -/- mice to DSS-induced colitis. TLR stimulation was sufficient to induce the expression of MTDH, whereas the absence of MTDH was sufficient to suppress TLR-induced production of inflammatory cytokines by macrophages. From a mechanistic perspective, MTDH recruited TRAF6 to TAK1, leading to TRAF6-mediated TAK1 K63 ubiquitination and phosphorylation, ultimately facilitating TLR-induced NF-κB and MAPK signaling. Taken together, our results indicate that MTDH contributes to colitis development by promoting TLR induced proinflammatory cytokines production in CLP macrophages and might represent a potential therapeutic approach for intestine inflammation intervention.