Scholarlink

<p>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.&#xa0;Acute colitis was induced by Dextran Sodium Sulfate (DSS) in wild-type and Nlrp12<sup>⁻/⁻</sup> mice. Disease severity was assessed by body weight, disease activity index, colon length, and histopathology. Tofacitinib (10&#xa0;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.&#xa0;Nlrp12<sup>⁻/⁻</sup> 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<sup>⁻/⁻</sup> 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<sup>⁻/⁻</sup> BMDMs.&#xa0;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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月9日

查看全文
  • Yun Yi,
  • Qiaofang Wei,
  • Siyu Chen,
  • Lurao Li,
  • Wangdron Dekyi,
  • Hangqi Jia,
  • Xiawen Shu,
  • Qiu Zhao,
  • Ying Chang

摘要

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.