美国加州大学旧金山分校Ronald D. Vale研究小组揭示，CD47连接使抑制性受体SIRPA重定位以抑制整合素激活和吞噬作用。该研究于2020年8月7日在线发表于《免疫》杂志。
研究人员利用一组已知组分的信号重构系统探索了SIRPA的激活机制及其下游靶点。CD47的连接改变了SIRPA的定位，将SIRPA定位在吞噬突触处进行激活。在吞噬突触处，SIRPA抑制整联蛋白的活化，从而限制了巨噬细胞在吞噬靶点表面的扩散。利用化学方法激活整联蛋白绕过了CD47介导的抑制作用，并恢复了吞噬作用，这类似于CD47功能阻断抗体的作用。
因此，CD47-SIRPA通路通过抑制巨噬细胞中整联蛋白信号由内而外的激活来抑制吞噬作用，这对癌症免疫疗法的应用产生了影响。
据了解，CD47充当“不吃我”信号，通过结合并激活巨噬细胞上的受体SIPRA来保护细胞免受吞噬作用。在不同的靶细胞上CD47抑制多个不同的促吞噬“吃我”信号，包括免疫球蛋白G（IgG）、补体和钙网蛋白。这种复杂性阻碍了人类对生化过程中“不吃我”信号的理解。
附：英文原文
Title: CD47 Ligation Repositions the Inhibitory Receptor SIRPA to Suppress Integrin Activation and Phagocytosis
Author: Meghan A. Morrissey, Nadja Kern, Ronald D. Vale
Issue&Volume: 2020-08-07
Abstract: CD47 acts as a “don’t eat me” signal that protects cells from phagocytosis by bindingand activating its receptor SIPRA on macrophages. CD47 suppresses multiple differentpro-engulfment “eat me” signals, including immunoglobulin G (IgG), complement, andcalreticulin, on distinct target cells. This complexity has limited understandingof how the “don’t eat me” signal is transduced biochemically. Here, we utilized areconstituted system with a defined set of signals to interrogate the mechanism ofSIRPA activation and its downstream targets. CD47 ligation altered SIRPA localization,positioning SIRPA for activation at the phagocytic synapse. At the phagocytic synapse,SIRPA inhibited integrin activation to limit macrophage spreading across the surfaceof the engulfment target. Chemical reactivation of integrin bypassed CD47-mediatedinhibition and rescued engulfment, similar to the effect of a CD47 function-blockingantibody. Thus, the CD47-SIRPA axis suppresses phagocytosis by inhibiting inside-outactivation of integrin signaling in the macrophage, with implications to cancer immunotherapyapplications.
DOI: 10.1016/j.immuni.2020.07.008
Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30315-0
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本期文章：《免疫》：Online/在线发表
