Inflammatory bowel disease (IBD) affects 0.3% of the global population, yet the etiology remains poorly understood. Anti-inflammation therapy has shown great success, but only 60% of patients with IBD benefit from it, indicating that new targets are needed. Here, we report the discovery of an intrinsic counter regulatory mechanism in colitis pathogenesis that may be targeted for IBD treatment. In response to microbial invasion, resident Vimentin⁺ stromal cells, connective tissue cells genetically marked by Twist2, are activated during the propagation phase of the disease, but not during initiation and resolution phases, and become a primary source of prostaglandin E₂ (PGE₂). PGE₂ induction requires a nuclear factor κB–independent, TLR4-p38MAPK-Cox2 pathway activation. Ablation of each of the pathway genes, but not Rela or Tgfb1, in Twist2 cells enhanced M1 macrophage polarization and granulocyte/T helper 1 (T_H1)/T_H17 infiltration and aggravated colitis development. PGE₂ administration ameliorated colitis in mouse models with defective PGE₂ production but not in animals with normal PGE₂ induction. Analysis of clinical samples and public domain data revealed increased expression of Cox2, the rate-limiting enzyme of PGE₂ biosynthesis, in inflamed tissues, and especially in colon Vimentin⁺Twist2⁺ stromal cells, in about 60% of patients with active Crohn’s disease or ulcerative colitis. Moreover, Cox2 protein expression was negatively correlated with disease severity, suggesting an involvement of stromal cells in IBD pathogenesis. Thus, the study uncovers an active immune pathway in colitic inflammation that may be targeted to treat patients with IBD with defects in PGE₂ production.

炎症性肠病 (IBD) 影响全球 0.3% 的人口，但其病因仍知之甚少。抗炎治疗显示出巨大的成功，但只有 60% 的 IBD 患者从中受益，这表明需要新的靶点。在这里，我们报告了可能针对 IBD 治疗的结肠炎发病机制中内在反调节机制的发现。响应微生物入侵，常驻波形蛋白⁺基质细胞，即由 Twist2 遗传标记的结缔组织细胞，在疾病的传播阶段被激活，但在开始和消退阶段不激活，并成为前列腺素 E ₂ (PGE ₂₎的主要来源）。铂族元素₂诱导需要独立于核因子 κB 的 TLR4-p38MAPK-Cox2 通路激活。在Twist2细胞中消融每个通路基因，但不是Rela或Tgfb1，增强了 M1 巨噬细胞极化和粒细胞/T 辅助 1 (T _H 1)/T _H 17 浸润和加重结肠炎发展。PGE ₂给药可改善 PGE ₂产生缺陷的小鼠模型中的结肠炎，但不能改善PGE ₂诱导正常的动物模型中的结肠炎。对临床样本和公共领域数据的分析显示，Cox2（PGE ₂生物合成的限速酶）在发炎组织中的表达增加，尤其是在结肠波形蛋白⁺Twist2 ⁺基质细胞，约 60% 的活动性克罗恩病或溃疡性结肠炎患者。此外，Cox2 蛋白表达与疾病严重程度呈负相关，表明基质细胞参与 IBD 发病机制。因此，该研究揭示了结肠炎炎症中的一个主动免疫途径，该途径可用于治疗 PGE ₂产生缺陷的 IBD 患者。