炎性破骨细胞以 TNFα 依赖性方式诱导结肠炎中髓质分化失调。

IF 7.9 2区 医学 Q1 IMMUNOLOGY
Maria-Bernadette Madel, Lidia Ibáñez, Thomas Ciucci, Julia Halper, Antoine Boutin, Ghada Beldi, Alice C Lavanant, Henri-Jean Garchon, Matthieu Rouleau, Christopher G Mueller, Laurent Peyrin-Biroulet, David Moulin, Claudine Blin-Wakkach, Abdelilah Wakkach
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引用次数: 0

摘要

炎症性肠病(IBD)的特点是非常严重的肠道炎症,并伴有肠道外表现。其中最关键的是骨质破坏,它仍然是 IBD 患者发病的主要原因,也是骨质疏松和骨质疏松症的危险因素。在各种 IBD 小鼠模型中,我们和其他研究人员已经证实,由于破骨细胞活性显著增加,骨质会同时流失。除了骨吸收外,破骨细胞还能控制体内造血龛和调节体外炎症反应,这表明它们可能参与体内慢性炎症。在这里,我们利用不同的结肠炎模型,发现抑制破骨细胞可显著减轻疾病的严重程度,而 RANKL 诱导破骨细胞分化则会导致疾病恶化。我们的研究结果表明,在结肠炎期间,破骨细胞的活性与肠道中髓样细胞的积聚之间存在直接联系。对结肠炎小鼠破骨细胞的 RNAseq 分析显示,参与造血干细胞龛重塑的基因过度表达。我们还证明,在结肠炎的早期阶段,破骨细胞诱导造血祖细胞增殖,并伴有骨髓偏斜,这在RANKL诱导的破骨细胞生成模型中得到了证实。从机制上讲,抑制 TNF-α 可减少 OCL 在体外和体内诱导的骨髓偏斜。最后,我们观察到,克罗恩病患者的破骨细胞活性与血液中髓样细胞的比例呈正相关。总之,我们的研究结果揭示了破骨细胞在体内结肠炎中的新作用,证明它们通过早期对造血的作用来发挥其结肠致病活性,导致维持肠道炎症的骨髓造血增加。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dysregulated myeloid differentiation in colitis is induced by inflammatory osteoclasts in a TNFα-dependent manner.

Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn's disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.

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来源期刊
Mucosal Immunology
Mucosal Immunology 医学-免疫学
CiteScore
16.60
自引率
3.80%
发文量
100
审稿时长
12 days
期刊介绍: Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.
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