Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer.
Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer.
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DOI：
10.1038/cdd.2016.11
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发表时间：
2016-06
影响因子：
12.4
通讯作者：
Herrmann M
中科院分区：
文献类型：
--
作者：
Birge RB;Boeltz S;Kumar S;Carlson J;Wanderley J;Calianese D;Barcinski M;Brekken RA;Huang X;Hutchins JT;Freimark B;Empig C;Mercer J;Schroit AJ;Schett G;Herrmann M
细胞凋亡是一种进化上保守且受到严格调控的细胞死亡方式。它通过在胚胎发生过程中雕刻复杂的组织，并通过去除已经达到高龄或基因组已经不可修复地损坏的无效细胞，在生理学中发挥重要作用。细胞凋亡的高潮是细胞吞噬作用（efferocytosis）迅速而果断地清除细胞尸体，这一术语用于区分凋亡细胞的吞噬与其他吞噬过程。在过去的几十年里，与efferocytosis相关的分子和细胞生物学事件得到了严格的研究，并确定了许多eat-me信号和受体。磷脂酰丝氨酸（PS）的外化可以说是最具代表性的进食信号，它反过来又与大量血清蛋白和调理素结合，从而促进efferocytosis。在生理条件下，外化PS作为一种显性的、进化保守的免疫抑制信号，促进耐受性，阻止局部和全身免疫激活。病理上，外化PS的先天免疫抑制作用被许多病毒、微生物和寄生虫劫持，促进感染，并在许多情况下建立感染潜伏期。PS在肿瘤微环境中也严重失调，并拮抗肿瘤免疫的发展。在这篇综述中，我们讨论了PS作为一种全局免疫抑制信号的生物学作用，以及PS如何被利用来驱动多种病理过程，如感染和癌症。最后，我们概述了靶向PS的药物在癌症和传染病治疗中具有重要价值的基本原理。
Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics.