CD47 acts as a “don’t eat me” signal that protects cells from phagocytosis by binding and activating its receptor SIPRA on macrophages. CD47 suppresses multiple different pro-engulfment “eat me” signals, including immunoglobulin G (IgG), complement, and calreticulin, on distinct target cells. This complexity has limited understanding of how the “don’t eat me” signal is transduced biochemically. Here, we utilized a reconstituted system with a defined set of signals to interrogate the mechanism of SIRPA 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 surface of the engulfment target. Chemical reactivation of integrin bypassed CD47-mediated inhibition and rescued engulfment, similar to the effect of a CD47 function-blocking antibody. Thus, the CD47-SIRPA axis suppresses phagocytosis by inhibiting inside-out activation of integrin signaling in the macrophage, with implications to cancer immunotherapy applications.

CD47 充当“别吃我”信号，通过结合并激活巨噬细胞上的受体 SIPRA 来保护细胞免遭吞噬。CD47 抑制不同靶细胞上多种不同的前吞噬“吃我”信号，包括免疫球蛋白 G (IgG)、补体和钙网蛋白。这种复杂性限制了人们对“别吃我”信号如何进行生化转导的理解。在这里，我们利用具有一组定义的信号的重构系统来询问 SIRPA 激活机制及其下游目标。CD47 连接改变了 SIRPA 定位，将 SIRPA 定位在吞噬突触处激活。在吞噬突触处，SIRPA 抑制整合素激活，以限制巨噬细胞在吞噬目标表面的扩散。整合素的化学再激活绕过了 CD47 介导的抑制并挽救了吞噬，类似于 CD47 功能阻断抗体的效果。因此，CD47-SIRPA 轴通过抑制巨噬细胞中整合素信号传导的由内而外激活来抑制吞噬作用，这对癌症免疫治疗应用具有影响。