Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Adolf-Reichwein Str. 23, 07745, Jena, Germany.
III. Medical Clinic, University Medical Center Hamburg-Eppendorf, Martini Str. 52, 20246, Hamburg, Germany.
Nat Commun. 2019 Jul 4;10(1):2961. doi: 10.1038/s41467-019-10766-0.
Persistent inflammation is a hallmark of many human diseases, including anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and atherosclerosis. Here, we describe a dominant trigger of inflammation: human serum factor H-related protein FHR1. In vitro, this protein selectively binds to necrotic cells via its N-terminus; in addition, it binds near necrotic glomerular sites of AAV patients and necrotic areas in atherosclerotic plaques. FHR1, but not factor H, FHR2 or FHR3 strongly induces inflammasome NLRP3 in blood-derived human monocytes, which subsequently secrete IL-1β, TNFα, IL-18 and IL-6. FHR1 triggers the phospholipase C-pathway via the G-protein coupled receptor EMR2 independent of complement. Moreover, FHR1 concentrations of AAV patients negatively correlate with glomerular filtration rates and associate with the levels of inflammation and progressive disease. These data highlight an unexpected role for FHR1 during sterile inflammation, may explain why FHR1-deficiency protects against certain diseases, and identifies potential targets for treatment of auto-inflammatory diseases.
持续的炎症是许多人类疾病的标志，包括抗中性粒细胞胞质抗体相关性血管炎（AAV）和动脉粥样硬化。在这里，我们描述了一个炎症的主要触发因素：人血清因子 H 相关蛋白 FHR1。在体外，这种蛋白质通过其 N 端选择性地与坏死细胞结合；此外，它还结合 AAV 患者肾小球坏死部位和动脉粥样硬化斑块的坏死区域。FHR1，但不是因子 H、FHR2 或 FHR3，强烈诱导血液来源的人单核细胞中的 NLRP3 炎症小体，随后分泌 IL-1β、TNFα、IL-18 和 IL-6。FHR1 通过 G 蛋白偶联受体 EMR2 触发磷脂酶 C 途径，而不依赖补体。此外，AAV 患者的 FHR1 浓度与肾小球滤过率呈负相关，并与炎症和进行性疾病的水平相关。这些数据突出了 FHR1 在无菌炎症中的意外作用，可能解释了为什么 FHR1 缺乏会预防某些疾病，并确定了治疗自身炎症性疾病的潜在靶点。
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