研究揭示CD47調控細胞吞噬的機制

研究揭示CD47調控細胞吞噬的機制

作者：

小柯機器人

發布時間：2020/8/10 14:46:31

美國加州大學舊金山分校Ronald D. Vale研究小組揭示，CD47連接使抑制性受體SIRPA重定位以抑制整合素激活和吞噬作用。該研究於2020年8月7日在線發表於《免疫》雜誌。

研究人員利用一組已知組分的信號重構系統探索了SIRPA的激活機制及其下遊靶點。CD47的連接改變了SIRPA的定位，將SIRPA定位在吞噬突觸處進行激活。在吞噬突觸處，SIRPA抑制整聯蛋白的活化，從而限制了巨噬細胞在吞噬靶點表面的擴散。利用化學方法激活整聯蛋白繞過了CD47介導的抑制作用，並恢復了吞噬作用，這類似於CD47功能阻斷抗體的作用。

因此，CD47-SIRPA通路通過抑制巨噬細胞中整聯蛋白信號由內而外的激活來抑制吞噬作用，這對癌症免疫療法的應用產生了影響。

據了解，CD47充當「不吃我」信號，通過結合併激活巨噬細胞上的受體SIPRA來保護細胞免受吞噬作用。在不同的靶細胞上CD47抑制多個不同的促吞噬「吃我」信號，包括免疫球蛋白G（IgG）、補體和鈣網蛋白。這種複雜性阻礙了人類對生化過程中「不吃我」信號的理解。

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