Crohn’s disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn’s disease^1,2, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment³. The risk alleles with the highest effect on Crohn’s disease are loss-of-function mutations in NOD2^4,5, which increase the risk of stricturing⁶. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14⁺ peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid–stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn’s disease, and suggest that gp130 blockade may benefit some patients with Crohn’s disease—potentially as a complement to anti-TNF therapy.

克罗恩病是一种慢性炎症性肠道疾病，通常伴有异常愈合和狭窄并发症。激活的髓细胞和基质细胞之间的串扰对克罗恩病^1,2的致病性至关重要，并且血管内单核细胞的增加与抗 TNF 治疗³缺乏反应相关。对克罗恩病影响最大的风险等位基因是NOD2中的功能丧失突变^4,5，这会增加狭窄的风险⁶. 然而，由 NOD2 突变驱动的致病机制以及可能挽救对抗 TNF 治疗缺乏反应的途径在很大程度上仍未得到表征。在这里，我们对携带NOD2风险等位基因的患者进行直接离体分析，以表明 NOD2 的缺失导致活化的成纤维细胞和巨噬细胞的稳态失调。来自NOD2风险等位基因携带者的CD14 ⁺外周血单个核细胞产生表达高水平胶原蛋白的细胞，并且在nod2-中观察到保守特征的升高肠道损伤的缺陷斑马鱼模型。STAT3 调节和 gp130 配体在活化的成纤维细胞和巨噬细胞中的富集表明 gp130 阻断可能挽救 NOD2 缺陷细胞中的活化程序。我们表明，STAT3 通路的治疗后诱导与患者对抗 TNF 治疗缺乏反应相关，并在斑马鱼体内证明了使用特异性 gp130 抑制剂巴多昔芬可改善活化的骨髓基质生态位。我们的研究结果为克罗恩病中 NOD2 驱动的纤维化提供了见解，并表明 gp130 阻断可能使一些克罗恩病患者受益——可能作为抗 TNF 治疗的补充。