NLRP12 Deficiency Enhances Tofacitinib Efficacy in DSS Colitis Via STAT1-M1 Polarization

作者：Yun Yi, Qiaofang Wei, Siyu Chen, Lurao Li, Wangdron Dekyi, Hangqi Jia, Xiawen Shu, Qiu Zhao, Ying Chang · 发表于：Inflammation · 年份：2026 · DOI：10.1007/s10753-026-02461-2 · 被引用次数：1 · 研究领域：Inflammatory Bowel Disease、Inflammasome and immune disorders、Immune cells in cancer

Tofacitinib, an oral pan-Janus kinase (JAK) inhibitor, induces rapid remission in ulcerative colitis (UC), but only ~60% of patients respond, highlighting the need for biomarkers to guide therapy. NLRP12, a NOD-like receptor, negatively regulates inflammation by restraining NF-κB signaling and modulating microbiota–host interactions. We hypothesized that NLRP12 deficiency skews macrophage polarization toward an M1-biased state dependent on JAK-STAT signaling, thereby enhancing responsiveness to JAK inhibition. Acute colitis was induced by Dextran Sodium Sulfate (DSS) in wild-type and Nlrp12 ⁻/⁻ mice. Disease severity was assessed by body weight, disease activity index, colon length, and histopathology. Tofacitinib (10 mg/kg) was administered orally from day 3 to 7. Macrophage infiltration and polarization (CD86⁺ M1, CD206⁺ M2) were assessed by flow cytometry, and STAT1 activation was measured in colon tissue and lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs) by Western blot. Nlrp12 ⁻/⁻ mice exhibited more severe DSS colitis, with elevated p-STAT1 levels, enhanced CD86⁺ M1 polarization, and reduced CD206⁺ M2 populations. Tofacitinib markedly ameliorated colitis in both genotypes but conferred greater benefit in Nlrp12 ⁻/⁻ mice, restoring weight, reducing histological damage, and selectively suppressing CD86⁺ M1 macrophages. In vitro, tofacitinib partially reversed the heightened STAT1 phosphorylation and M1 polarization in Nlrp12 ⁻/⁻ BMDMs. NLRP12 ...