Nature:靶向gp130或可用于抗TNF治疗无效的克罗恩病
创作:szx 审核:szx 04月02日
  • 携带NOD2功能缺失突变的克罗恩病患者中,活化成纤维细胞及炎症巨噬细胞中的WT1及STAT3等上游转录因子富集,以上调NOD2缺陷相关的促炎及促纤维化因子;
  • 缺失NOD2的CD14+ PBMC可产生更多的胶原高表达细胞;
  • 抗TNF治疗不应答患者的IL-11、OSM、IL-6等gp130家族基因表达升高;
  • 在斑马鱼中,NOD2缺失导致相似的髓系细胞-基质细胞活化表型,gp130抑制剂缓解DSS诱导的肠道炎症,并降低白细胞浸润及WT1等的表达(在NOD2缺失个体中更为明显)。
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szx
活化的髓系细胞与基质细胞的互作在克罗恩病的发病机制中十分关键,单核细胞浸润的增加与患者对抗TNF治疗的不应答相关。NOD2的功能缺失突变是克罗恩病的风险基因位点,可增加肠道狭窄的风险。来自Nature上发表的一项最新研究,发现在克罗恩病患者、健康人及斑马鱼模型中,NOD2的功能缺失突变可导致活化成纤维细胞及炎症巨噬细胞的稳态失调,表现为由WT1及STAT3等上游转录因子上调引起的异常活化相关转录组的表达增加,而NOD2缺陷导致的gp130家族基因(IL-11、IL-6、OSM等)的表达上调可能使克罗恩病患者对抗TNF治疗不应答。在斑马鱼模型中,gp130抑制剂bazedoxifene可显著缓解DSS诱导的肠道炎症,且抗炎作用在NOD2缺失个体中更为明显。该研究结果揭示了NOD2功能缺失突变驱动克罗恩病纤维化的新机制,并提示gp130抑制剂或可用于对抗TNF治疗不应答的克罗恩病患者的治疗。
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Nature [IF:42.778]

A myeloid–stromal niche and gp130 rescue in NOD2-driven Crohn’s disease

抑制gp130可恢复NOD2驱动的克罗恩病中的活化髓系细胞-基质细胞生态位

10.1038/s41586-021-03484-5

03-31, Article

Abstract & Authors:展开

Abstract:收起
Crohn’s disease (CD) is a chronic inflammatory intestinal disease, with frequent aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in pathogenicity1,2 with increases in intravasating monocytes correlated to anti-TNF treatment non-response3. The highest effect risk alleles are loss-of-function NOD24,5 mutations, which increase risk for stricturing6. However, mechanisms underlying NOD2-pathogenicity and salvage pathways in anti-TNF refractory patients remain largely uncharacterized. Here we show that NOD2 loss leads to dysregulated activated fibroblast and macrophage homeostasis by direct ex vivo analyses of patients carrying NOD2 risk alleles. CD14+PBMCs from NOD2 carriers produce collagen-high expressing cells, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. Enrichment of STAT3 regulation and gp130-ligands in activated fibroblasts and macrophages led us to reason that gp130 blockade might rescue the activated program. We correlate post-treatment induction of this pathway in anti-TNF non-responders and demonstrate in vivo amelioration of the activated myeloid-stromal niche, using a specific gp130 inhibitor, bazedoxifene. Our results demonstrate novel biological insights into NOD2-driven fibrosis in CD; gp130 blockade may benefit selected CD patients, potentially complementing anti-TNF therapy.

First Authors:
Shikha Nayar

Correspondence Authors:
Judy H Cho

All Authors:
Shikha Nayar,Joshua K Morrison,Mamta Giri,Kyle Gettler,Ling-shiang Chuang,Laura A Walker,Huaibin M Ko,Ephraim Kenigsberg,Subra Kugathasan,Miriam Merad,Jaime Chu,Judy H Cho

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