Macrophages polarization is critical in the pathogenesis of ulcerative colitis (UC). However, the endogenous regulators of this process remain poorly understood. Here, we investigate the role of the damage-associated molecular pattern (DAMP), N-myc and STAT interactor (NMI), in driving pro-inflammatory (M1) macrophages polarization and UC progression. Analysis of three of independent inflammatory bowel disease (IBD) transcriptomic datasets revealed a significant upregulation of NMI expression in UC patients, with prominent enrichment in macrophages and epithelial cells, a finding recapitulated in dextran sulfate sodium (DSS)-induce murine colitis model. Mice with Nmi gene knock-out (Nmi−/−) were protected from both acute and chronic colitis, exhibiting reduced intestinal M1 macrophages infiltration and low pro-inflammatory cytokine levels. Mechanistically, in vitro studies demonstrate that recombinant NMI promoted M1 macrophages polarization via TLR4-dependent MAPK/AP1 signaling pathway. Therapeutically, administration of an NMI-neutralizing antibody significantly ameliorated colitis by reprogramming the macrophage balance, reducing pro-inflammatory M1 accumulation while increasing anti-inflammatory M2 subsets. Collectively, our study establishes NMI as a key regulator of pro-inflammatory macrophage polarization and highlights its potential as a novel therapeutic target for UC.
Yang et al. (Fri,) studied this question.