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科学家发现治疗NOD2型克罗恩病的新方法
作者:小柯机器人 发布时间:2021/4/4 22:50:20

美国西奈山伊坎医学院Judy H. Cho研究组发现治疗NOD2型克罗恩病的新方法。这一研究成果于2021年3月31日在线发表在国际学术期刊《自然》上。

研究人员表示,克罗恩氏病(CD)是一种慢性炎症肠病,具有频繁的异常愈合和狭窄并发症。活化的髓样细胞和基质细胞之间的串扰在致病性方面至关重要,并且与抗TNF治疗无反应相关的血管内单核细胞增多。风险最高的等位基因是功能缺失的NOD2突变,增加了狭窄的风险。但是,抗TNF难治性患者中NOD2致病性和挽救途径的潜在机制仍未完全阐明。

通过对携带NOD2风险等位基因的患者进行直接离体分析,研究人员表明NOD2的丢失导致活化成纤维细胞和巨噬细胞稳态的失调。NOD2携带着的CD14+PBMC产生胶原蛋白高表达的细胞,并且研究人员在nod2缺陷型斑马鱼肠道损伤模型中观察到了保守标记的升高。在激活的成纤维细胞和巨噬细胞中,STAT3调控和gp130-配体的富集使研究人员推断gp130阻断可能会拯救激活的程序。研究人员使用特定的gp130抑制剂巴泽多昔芬(Bazedoxifene)证明了激活后骨髓基质微环境的体内改善。这些结果证明了CD中由NOD2驱动的纤维化。gp130阻断剂可能会使特定的CD患者受益,并可能会补充抗TNF疗法。 

附:英文原文

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

Author: 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

Issue&Volume: 2021-03-31

Abstract: 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.

DOI: 10.1038/s41586-021-03484-5

Source: https://www.nature.com/articles/s41586-021-03484-5

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html