Laboratory of Biochemistry & Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
Int Immunol. 2018 Nov 14;30(12):551-558. doi: 10.1093/intimm/dxy055.
An enormous number of cells in the body die by apoptosis during development and under homeostasis. Apoptotic cells are swiftly engulfed by macrophages and digested into units. This removal of apoptotic cells is called 'efferocytosis'. For efferocytosis, macrophages recognize phosphatidylserine (PtdSer) exposed on the cell surface as an 'eat me' signal. In healthy cells, PtdSer is exclusively localized to the inner leaflet of the plasma membrane by the action of flippases. When cells undergo apoptosis, caspase cleaves flippases to inactivate them, while it cleaves pro-scramblases to active scramblases, which quickly translocate PtdSer to the cell surface. The PtdSer is then recognized by PtdSer-binding proteins or by PtdSer receptors on macrophages, which subsequently engulf the apoptotic cells. When efferocytosis fails, apoptotic cells can rupture, releasing cellular materials that can evoke an autoimmune response. Thus, a defect in the PtdSer-exposing or PtdSer-recognizing processes triggers autoimmunity, leading to a systemic lupus erythematosus-type autoimmune disease.
在发育和体内平衡过程中，体内大量细胞通过细胞凋亡而死亡。凋亡细胞迅速被巨噬细胞吞噬并消化成小体。这种凋亡细胞的清除称为“噬作用”。对于噬作用，巨噬细胞识别细胞表面暴露的磷脂酰丝氨酸（PtdSer）作为“吃我”信号。在健康细胞中，磷脂酰丝氨酸（PtdSer）通过翻转酶的作用专门定位于质膜的内叶。当细胞发生凋亡时，半胱天冬酶裂解翻转酶使其失活，同时裂解前斑酶使其变为斑酶，后者迅速将 PtdSer 转位到质膜表面。然后 PtdSer 被巨噬细胞上的 PtdSer 结合蛋白或 PtdSer 受体识别，随后吞噬凋亡细胞。当噬作用失败时，凋亡细胞可能破裂，释放出可引发自身免疫反应的细胞物质。因此，PtdSer 暴露或 PtdSer 识别过程的缺陷会引发自身免疫，导致全身性红斑狼疮样自身免疫性疾病。
