Fig. 2

Microglia recognize apoptotic cell processes. Microglia are recruited to the vicinity of ACs, where they recognize “Eat-Me” signals displayed on the membranes of these cells, initiating phagocytosis through direct or indirect interactions. Following apoptosis, “Eat-Me” signals such as phosphatidylserine (PS) and calreticulin (CRT) become exposed on the cell surface, interacting with receptors on microglia either directly or indirectly. Receptors that interact directly with PS include T cell immunoglobulin and mucin domain-containing protein 4 (TIM4), brain angiogenesis inhibitor 1 (BAI1), receptor for advanced glycation end products (RAGE), and stabilin-2 (Stab2). The TAM receptor tyrosine kinases, which include TYRO3, AXL, and Mer receptor tyrosine kinase (MERTK), recognize PS through specific bridging ligands such as growth arrest-specific 6 (Gas6) and Protein S. Additionally, integrins αvβ3 and αvβ5 recognize ACs via the bridging molecule milk fat globule-epidermal growth factor 8 (MFGE8). Activated microglia also express low-density lipoprotein receptor-related protein 1 (LRP1), which directly interacts with calreticulin on the surface of ACs. In contrast, healthy cells display “Don’t-Eat-Me” signals, such as CD47, on their surfaces. CD47 binds to the regulatory protein alpha (SIRPα) on microglia, leading to the tyrosine phosphorylation of the cytoplasmic domain of SIRPα and the recruitment of SHP1/2, which inhibits phagocytosis. TYRO3: TYRO3 protein tyrosine kinase. AXL: AXL protein tyrosine kinase. MERTK: Mer receptor tyrosine kinase. Gas6: growth arrest-specific 6