NMI Promotes Pro-Inflammatory Macrophage Polarization and Exacerbates

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.