Fig. 2.

Key players during efferocytosis in CVD. Efferocytosis requires the interplay between numerous cellular and extracellular ligands. At the level of the apoptotic cells (AC), presentation of “eat-me” signals [such as phosphatidylserine (ps)] and down-regulation of “don’t-eat” me ligands (such as CD47, CD31, and PAI-1) prepare apoptotic cell ligands for engulfment by macrophage (MU) and immature and mature dendritic (IDC and DC) phagocyte subsets. Neutrophils (PMN) may act as phagocytes and/or apoptotic cells. Interactions between apoptotic target and phagocyte effector often require ‘‘bridging’’ molecules such as Gas6/protein S, lactadherin (MFGE8), complement (C1q, C3b), calreticulin (cal), annexin (anxII), and immunoglobulin (IgM) to facilitate target-effector juxtaposition. Numerous apoptotic cell receptors [such as scavenger receptor A (SRA), TAMs, integrins, LRP, and CD36] and signaling (CrkII-Dock180-Rac1, Rho/actin) and metabolic (NR nuclear receptors) molecules participate during engulfment and modulate downstream inflammatory signaling pathways. “Necrotic” indicates secondary necrotic cells. Arrows indicate differentiation pathways from immature monocyte and dendritic cell precursors. ACAMP apoptotic cell-associated molecular pattern, AC apoptotic cell, MO: monocyte, IDC immature dendritic cell, DC dendritic cell, PAI-1 plasminogen activator inhibitor-1, PMN polymorphonuclear leukocyte or neutrophil, PS phosphatidylserine, TAM Tyro3, Axl tyrosine kinase, MerTK