Mini‐review: A pivotal role for innate immunity in the clearance of apoptotic cells

Abstract

Apoptotic cells can be recognized and taken up by both macrophages and dendritic cells. Phagocytosis of apoptotic cells generally leads to active suppression of cytokine production by professional phagocytes. This is different from the response towards cells that die by necrosis, which induce a pro-inflammatory cytokine profile. Uptake of apoptotic cells involves a large number of receptors and opsonins, which bind to cellular ligands exposed during the various stages of apoptotic cell death. Among the opsonins of apoptotic cells, complement factors, including C1q, and complement-activating members of the pentraxin family play an important role. This is indicated by in vitro phagocytosis studies and supported by the susceptibility to systemic autoimmunity of carriers of genetic deficiencies for early complement proteins. The present review summarizes the role of molecules of innate immunity in the handling of apoptotic cells by macrophages and dendritic cells. It is proposed that C1q and other opsonins prevent autoimmunity and maintain self-tolerance by supporting the efficient clearance of apoptotic material, as well as by actively modulating phagocyte function.

The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis

“…Complement activation can be triggered via three pathways, the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP), each culminating in the formation of the surface-bound C3 convertases and C3b opsonization. According to the current paradigm, recognition of apoptotic cells is initiated through the CP and/or LP, which in turn activates the AP (12,15,(17)(18)(19).…”

Candidate inhibitors of porcine complement

“…C4b2a cleaves C3 to C3a and C3b and forms the C5 convertase The main function of the complement system is to detect and kill microorganisms, as well as maintain homeostasis through clearance of apoptotic cells and cell debris, and tissue regeneration (65)(66)(67)(68). Opsonization by C3b leading to phagocytosis is the most important mechanism, but for some pathogens like Neisseria-species, killing by direct lysis by the MAC is equally important (69).…”

“…The products of the complement system have however a number of other effects. C5a is an important mediator of inflammation as discussed later, and TCC and other complement proteins are involved in cell death (apoptosis and necrosis), clearance of apoptotic cells and cell activation (66,70). A number of soluble and cell-bound regulatory proteins act to inhibit the complement system, keeping it under tight control (71).…”

Mannose-Binding Lectin-Deficient Mice Display Defective Apoptotic Cell Clearance but No Autoimmune Phenotype

“…Furthermore, SPD null animals have defective in vivo clearance of apoptotic cells in the lung (14). These observations suggest that MBL could also have a role in apoptotic cell clearance in vivo and, along with the reports of increased risk of autoimmunity in MBL low individuals (6,7), have raised the question of whether lack of MBL might result in autoimmunity as is observed with C1q deficiency (15). To study the role of MBL in vivo, we have generated mice deficient in both genes encoding mouse MBL (MBLA and MBLC) (3), and here we report the role of MBL in autoimmunity.…”