Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis.
Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis.
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DOI：
10.1016/j.immuni.2023.06.026
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发表时间：
2023-07
期刊：
影响因子：
32.4
通讯作者：
Máté G Kiss;N. Papac-Miličević;F. Porsch;D. Tsiantoulas;T. Hendrikx;M. Takaoka;Huy Q. Dinh;M. Narzt;L. Göderle;M. Ozsvár-Kozma;M. Schuster;N. Fortelny;A. Hladik;S. Knapp;F. Gruber;M. Pickering;C. Bock;F. Swirski;K. Ley;A. Zernecke;C. Cochain;C. Kemper;Z. Mallat;C. Binder
中科院分区：
文献类型：
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作者：
Máté G Kiss;N. Papac-Miličević;F. Porsch;D. Tsiantoulas;T. Hendrikx;M. Takaoka;Huy Q. Dinh;M. Narzt;L. Göderle;M. Ozsvár-Kozma;M. Schuster;N. Fortelny;A. Hladik;S. Knapp;F. Gruber;M. Pickering;C. Bock;F. Swirski;K. Ley;A. Zernecke;C. Cochain;C. Kemper;Z. Mallat;C. Binder
补体因子H（CFH）负调节补体成分3（C3）的消耗，从而限制补体激活。CFH的遗传变异易患慢性炎症性疾病。在这里，我们研究了CFH对动脉粥样硬化发展的影响。在动脉粥样硬化的小鼠模型中，CFH缺乏以C3依赖的方式限制斑块坏死。在单核细胞衍生的炎性巨噬细胞中CFH的缺失传播了不受控制的细胞自主C3消耗，而没有下游C5活化和提高的细胞吞噬能力。在白细胞中，Cfh表达仅限于单核细胞和巨噬细胞，在炎症过程中增加，并与细胞内C3的积累相一致。巨噬细胞衍生的CFH足以抑制炎症的消退，并且在动脉粥样硬化倾向小鼠中CFH的造血缺失促进了损伤性红细胞增多并减小了斑块大小。此外，我们确定了单核细胞衍生的炎症巨噬细胞表达C3和CFH在人类动脉粥样硬化斑块。我们的研究结果揭示了一个调节轴，其中CFH控制细胞内C3水平的巨噬细胞在细胞自主的方式，证明了现场补体调节的重要性，在炎症性疾病的发病机制。
Complement factor H (CFH) negatively regulates consumption of complement component 3 (C3), thereby restricting complement activation. Genetic variants inCFHpredispose to chronic inflammatory disease. Here, we examined the impact of CFH on atherosclerosis development. In a mouse model of atherosclerosis, CFH deficiency limited plaque necrosis in a C3-dependent manner. Deletion of CFH in monocyte-derived inflammatory macrophages propagated uncontrolled cell-autonomous C3 consumption without downstream C5 activation and heightened efferocytotic capacity. Among leukocytes,Cfhexpression was restricted to monocytes and macrophages, increased during inflammation, and coincided with the accumulation of intracellular C3. Macrophage-derived CFH was sufficient to dampen resolution of inflammation, and hematopoietic deletion of CFH in atherosclerosis-prone mice promoted lesional efferocytosis and reduced plaque size. Furthermore, we identified monocyte-derived inflammatory macrophages expressing C3 and CFH in human atherosclerotic plaques. Our findings reveal a regulatory axis wherein CFH controls intracellular C3 levels of macrophages in a cell-autonomous manner, evidencing the importance of on-site complement regulation in the pathogenesis of inflammatory diseases.