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 deficiency enhances macrophage JAK-STAT1 activation, increasing sensitivity to tofacitinib due to a proinflammatory M1-dominant state. This suggests that a high M1/M2 ratio and elevated p-STAT1 could guide JAK inhibitor therapy in UC, though their predictive value requires human validation. Targeting NLRP12 or macrophage polarization may optimize treatment outcomes.
Yi et al. (Sun,) studied this question.