The β2 Integrin Mac-1 Induces Protective LC3-Associated Phagocytosis of Listeria monocytogenes
The β2 Integrin Mac-1 Induces Protective LC3-Associated Phagocytosis of Listeria monocytogenes
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DOI：
10.1016/j.chom.2018.01.018
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发表时间：
2018-03-14
影响因子：
30.3
通讯作者：
Schramm, Michael
中科院分区：
文献类型：
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作者：
Gluschko, Alexander;Herb, Marc;Schramm, Michael
细胞内病原体单核细胞增生李斯特菌 (L.m.) 是自噬机制的目标，但所涉及的分子机制和抗李斯特菌免疫的后果仍然是个谜。在这里，我们证明 L.m.体内巨噬细胞的感染只会引起 LC3 相关的吞噬作用 (LAP)，但不会引起典型的自噬，并且针对 L.m. LAP 是抗李斯特菌免疫所必需的。响应 L.m. 导致 LAP 诱导的途径。感染源自β(2) 整合素Mac-1（CR3，整合素α(M)β(2)），这是一种识别多种微生物配体的受体。 L.m. 的互动与 Mac-1 一起诱导酸性鞘磷脂酶介导的膜脂成分变化，促进吞噬细胞 NAPDH 氧化酶 Nox2 的组装和激活。 Nox2 衍生的活性氧随后通过 LAP 触发 LC3 募集至含有 L.m. 的吞噬体。通过促进含有 L.m. 的吞噬体与溶酶体的融合，LAP 增加了 L.m. 的暴露。杀菌酸性水解酶，从而增强巨噬细胞的抗李斯特菌活性和小鼠的免疫力。
The intracellular pathogen Listeria monocytogenes (L.m.) is targeted by the autophagic machinery, but the molecular mechanisms involved and consequences for anti-listerial immunity remain enigmatic. Here, we demonstrate that L.m. infection of macrophages in vivo exclusively evokes LC3-associated phagocytosis (LAP), but not canonical autophagy, and that targeting of L.m. by LAP is required for anti-listerial immunity. The pathway leading to LAP induction in response to L.m. infection emanates from the beta(2) integrin Mac-1 (CR3, integrin alpha(M)beta(2)), a receptor recognizing diverse microbial ligands. Interaction of L.m. with Mac-1 induces acid sphingomye-linase-mediated changes in membrane lipid composition that facilitate assembly and activation of the phagocyte NAPDH oxidase Nox2. Nox2-derived reactive oxygen species then trigger LC3 recruitment to L.m.-containing phagosomes by LAP. By promoting fusion of L.m.-containing phagosomes with lysosomes, LAP increases exposure of L.m. to bactericidal acid hydrolases, thereby enhancing anti-listerial activity of macrophages and immunity of mice.