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奥地利维也纳医科大学Christoph J. Binder等研究人员合作发现，H因子对补体C3的细胞自主调节限制巨噬细胞胞葬作用并加剧动脉粥样硬化。2023年7月26日，《免疫》杂志在线发表了这项成果。

研究人员报道了补体因子H（CFH）对动脉粥样硬化进展的影响。在动脉粥样硬化小鼠模型中，CFH缺乏以补体成分3（C3）依赖性方式限制了斑块坏死。在单核细胞衍生的炎性巨噬细胞中缺失CFH会导致细胞自主的C3消耗失控，而不会激活下游的C5，并增强了胞葬能力。在白细胞中，Cfh的表达仅限于单核细胞和巨噬细胞，在炎症期间会增加，并与细胞内C3的积累同时发生。巨噬细胞来源的CFH足以抑制炎症的消退，动脉粥样硬化易感小鼠造血中CFH的缺失可促进病变的胞葬作用并缩小斑块。

此外，研究人员还在人类动脉粥样硬化斑块中发现了表达C3和CFH的单核细胞衍生炎性巨噬细胞。这些研究结果揭示了一个调控轴，其中CFH以细胞自主的方式控制巨噬细胞内的C3水平，并证明了补体调控在炎症性疾病发病机制中的重要性。

据介绍，CFH对C3的消耗起负性调节作用，从而限制补体激活。CFH的基因变异易导致慢性炎症性疾病。

附：英文原文

Title: Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis

Author: Máté G. Kiss, Nikolina Papac-Milievi, Florentina Porsch, Dimitrios Tsiantoulas, Tim Hendrikx, Minoru Takaoka, Huy Q. Dinh, Marie-Sophie Narzt, Laura Gderle, Mária Ozsvár-Kozma, Michael Schuster, Nikolaus Fortelny, Anastasiya Hladik, Sylvia Knapp, Florian Gruber, Matthew C. Pickering, Christoph Bock, Filip K. Swirski, Klaus Ley, Alma Zernecke, Clément Cochain, Claudia Kemper, Ziad Mallat, Christoph J. Binder

Issue&Volume: 2023-07-26

Abstract: Complement factor H (CFH) negatively regulates consumption of complement component3 (C3), thereby restricting complement activation. Genetic variants in CFH predispose to chronic inflammatory disease. Here, we examined the impact of CFH onatherosclerosis development. In a mouse model of atherosclerosis, CFH deficiency limitedplaque necrosis in a C3-dependent manner. Deletion of CFH in monocyte-derived inflammatorymacrophages propagated uncontrolled cell-autonomous C3 consumption without downstreamC5 activation and heightened efferocytotic capacity. Among leukocytes, Cfh expression was restricted to monocytes and macrophages, increased during inflammation,and coincided with the accumulation of intracellular C3. Macrophage-derived CFH wassufficient to dampen resolution of inflammation, and hematopoietic deletion of CFHin atherosclerosis-prone mice promoted lesional efferocytosis and reduced plaque size.Furthermore, we identified monocyte-derived inflammatory macrophages expressing C3and CFH in human atherosclerotic plaques. Our findings reveal a regulatory axis whereinCFH controls intracellular C3 levels of macrophages in a cell-autonomous manner, evidencingthe importance of on-site complement regulation in the pathogenesis of inflammatorydiseases.

DOI: 10.1016/j.immuni.2023.06.026

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00283-2

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