Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells.
Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells.
复制标题
非规范自噬抑制自身炎症，类似狼疮的对垂死细胞的反应。
DOI：
10.1038/nature17950
复制
发表时间：
2016-05-05
期刊：
影响因子：
64.8
通讯作者：
Green DR
中科院分区：
文献类型：
--
作者：
Martinez J;Cunha LD;Park S;Yang M;Lu Q;Orchard R;Li QZ;Yan M;Janke L;Guy C;Linkermann A;Virgin HW;Green DR
死亡细胞清除的缺陷被认为是系统性红斑狼疮（SLE）发病机制的基础。缺乏与死亡细胞清除相关的分子的小鼠发展成SLE样疾病，并且来自SLE患者的吞噬细胞在体外暴露于死亡细胞时通常显示出有缺陷的清除和增加的炎性细胞因子产生。以前，我们和其他人描述了一种称为“LC 3相关吞噬作用”（LC 3-associated phagocytosis）的非经典自噬形式，其中含有吞噬颗粒（包括垂死细胞）的吞噬体招募自噬途径的元件，以促进吞噬体成熟和货物消化。全基因组关联研究已经确定了atg 5和可能的atg 7的多态性，参与了典型的自噬和tumor，作为SLE的易感性标志物。在这里，我们描述的后果，有缺陷的在体内。缺乏任何一种α-淀粉样蛋白途径成分的小鼠表现出血清炎性细胞因子、自身抗体、肾小球免疫复合物沉积升高和肾损伤的迹象。注射到LAP缺陷动物中的死亡细胞被吞噬但不能有效降解，并触发促炎细胞因子的急性升高，但不触发抗炎白细胞介素（IL）-10。重复注射垂死细胞到LAP缺陷，但不是LAP充足的动物加速SLE样疾病，包括增加血清自身抗体水平。相比之下，缺乏典型自噬所需基因但不缺乏凋亡基因的动物不显示有缺陷的死细胞清除、炎性细胞因子产生或SLE样疾病，并且像野生型动物一样，响应于死亡细胞产生IL-10。因此，在SLE的发病机制，而不是典型的自噬缺陷，可导致SLE样现象，并可能有助于SLE的发病机制。
Defects in dying cell clearance are postulated to underlie the pathogenesis of systemic lupus erythematosus (SLE). Mice lacking molecules associated with dying cell clearance develop SLE-like disease, and phagocytes from SLE patients often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we and others described a form of noncanonical autophagy called “LC3-associated phagocytosis” (LAP), wherein phagosomes containing engulfed particles, including dying cells, recruit elements of the autophagy pathway to facilitate phagosome maturation and digestion of cargo. Genome-wide association studies have identified polymorphisms in atg5 and possibly atg7, involved in both canonical autophagy and LAP, as predisposition markers for SLE. Here, we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway display elevated serum inflammatory cytokines, autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. Dying cells, injected into LAP-deficient animals, are engulfed but not efficiently degraded, and trigger acute elevation of pro-inflammatory cytokines but not the anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient animals accelerated SLE-like disease, including increased serum levels of autoantibodies. In contrast, animals deficient for genes required for canonical autophagy but not LAP do not display defective dead cell clearance, inflammatory cytokine production, or SLE-like disease, and like wild-type animals, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE.