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载脂蛋白C3在炎症中的新功能
2019-12-10 15:12

德国萨尔兰大学Thimoteus Speer研究组发现,载脂蛋白C3通过替代激活炎性小体诱导炎症和器官损伤。该研究2019年12月9日在线发表在国际学术期刊《自然—免疫学》上。

研究人员发现载脂蛋白C3(ApoC3)通过caspase-8和Toll样受体2和4二聚化的方式诱导NLRP3炎性小体的替代激活,从而激活了人单核细胞中的NLRP3炎性小体。人单核细胞中炎性小体的替代激活受Toll样受体蛋白SCIMP的调控。这种激活引起Lyn / Syk依赖的钙离子进入和活性氧的产生,导致caspase-8的活化。在人源化的小鼠模型中,ApoC3在体内以NLRP3和caspase-8依赖性方式激活人单核细胞从而阻止内皮再生并促进肾脏损伤。这些数据为NLRP3炎性小体的调控以及富含ApoC3的甘油三酯脂蛋白的生理病理作用提供了新的见解。靶向ApoC3可以防止器官损伤并为血管和肾脏疾病提供了新的抗炎治疗策略。

据了解,NLRP3-炎性小体诱导的炎症与多种疾病的发生有关。内源炎性小体激活剂的鉴定对于开发新的抗炎治疗策略至关重要。

附:英文原文

Title: Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation

Author: Stephen Zewinger, Jochen Reiser, Vera Jankowski, Dalia Alansary, Eunsil Hahm, Sarah Triem, Mira Klug, Stefan J. Schunk, David Schmit, Rafael Kramann, Christina Krbel, Emmanuel Ampofo, Matthias W. Laschke, Simina-Ramona Selejan, Anna Paschen, Tobias Herter, Susanne Schuster, Gnther Silbernagel, Martina Sester, Urban Sester, Gunter Amann, Robert Bals, Gerhard Kostner, Willi Jahnen-Dechent, Michael D. Menger, Lucia Rohrer, Winfried Mrz, Michael Bhm, Joachim Jankowski, Manfred Kopf, Eicke Latz, Barbara A. Niemeyer, Danilo Fliser, Ulrich Laufs, Thimoteus Speer

Issue&Volume: 2019-12-09

Abstract: NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.

DOI: 10.1038/s41590-019-0548-1

Source: https://www.nature.com/articles/s41590-019-0548-1

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex


本期文章:《自然—免疫学》:Online/在线发表

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