小柯机器人

近日，德国埃尔朗根大学Markus H. Hoffmann及其研究小组发现，补体系统通过滑膜成纤维细胞的代谢重编程来驱动局部炎症组织的产生。这一研究成果于2021年3月23日在线发表在国际学术期刊《免疫》上。

研究人员定义了一种炎症介导组织活化的分子和细胞机制。在啮齿动物模型中再次暴露于炎症刺激会导致关节炎加剧。组织活化在局部发展，与适应性免疫无关。反复刺激的引发性滑膜成纤维细胞（SFs）表现出增强的代谢活性，并随着迁移、侵袭性和破骨细胞生成的增强而引起功能变化。同时，来自患有关节炎的患者的人SF表现出相似的致敏表型。

转录组学和表观基因组学分析以及遗传和药理学靶向研究表明，炎症组织引发依赖于胞内补体C3-和C3a受体激活以及雷帕霉素和低氧诱导因子1α介导的下游SF介导的代谢SF活化，从而阻止了活化诱导衰老，增强NLRP3炎性体活性，并因此使组织对炎症敏感。

这项研究表明，在不进行免疫抑制的情况下，进行治疗干预可以消除组织致敏性。 

据介绍，关节炎通常在特定的好发部位，并出现复发和进行性恶化，但是缓解和持续性之间的检查点仍然未知。

附：英文原文

Title: The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts

Author: Jasna Frii, Martin Bttcher, Christiane Reinwald, Heiko Bruns, Benjamin Wirth, Samantha-Josefine Popp, Kellie Irene Walker, Jochen A. Ackermann, Xi Chen, Jason Turner, Honglin Zhu, Lisa Seyler, Maximilien Euler, Philipp Kirchner, René Krüger, Arif B. Ekici, Triin Major, Oliver Aust, Daniela Weidner, Anita Fischer, Fabian T. Andes, Zeljka Stanojevic, Vladimir Trajkovic, Martin Herrmann, Adelheid Korb-Pap, Isabel Wank, Andreas Hess, Johnathan Winter, Viktor Wixler, Jrg Distler, Günter Steiner, Hans P. Kiener, Benjamin Frey, Lasse Kling, Karim Raza, Silke Frey, Arnd Kleyer, Tobias Buerle, Timothy R. Hughes, Anika Grüneboom, Ulrike Steffen, Gerhard Krnke, Adam P. Croft, Andrew Filer, Jrg Khl, Kerstin Klein, Christopher D. Buckley, Georg Schett, Dimitrios Mougiakakos, Markus H. Hoffmann

Issue&Volume: 2021-03-23

Abstract: Arthritis typically involves recurrence and progressive worsening at specific predilectionsites, but the checkpoints between remission and persistence remain unknown. Here,we defined the molecular and cellular mechanisms of this inflammation-mediated tissuepriming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodentmodels. Tissue priming developed locally and independently of adaptive immunity. Repeatedlystimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activityinducing functional changes with intensified migration, invasiveness and osteoclastogenesis.Meanwhile, human SF from patients with established arthritis displayed a similar primedphenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacologicaltargeting demonstrated that inflammatory tissue priming relies on intracellular complementC3- and C3a receptor-activation and downstream mammalian target of rapamycin- andhypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-inducedsenescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissuefor inflammation. Our study suggests possibilities for therapeutic intervention abrogatingtissue priming without immunosuppression.

DOI: 10.1016/j.immuni.2021.03.003

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00115-1

Immunity：《免疫》，创刊于1994年。隶属于细胞出版社，最新IF：43.474
官方网址：https://www.cell.com/immunity/home
投稿链接：https://www.editorialmanager.com/immunity/default.aspx