Efferocytosis and Its Role in Inflammatory Disorders

Abstract

Efferocytosis is the effective clearance of apoptotic cells by professional and non-professional phagocytes. The process is mechanically different from other forms of phagocytosis and involves the localization, binding, internalization, and degradation of apoptotic cells. Defective efferocytosis has been demonstrated to associate with the pathogenesis of various inflammatory disorders. In the current review, we summarize recent findings with regard to efferocytosis networks and discuss the relationship between efferocytosis and different immune cell populations, as well as describe how efferocytosis helps resolve inflammatory response and modulate immune balance. Our knowledge so far about efferocytosis suggests that it may be a useful target in the treatment of numerous inflammatory diseases.

Keywords: apoptosis; efferocytosis; immune response; inflammatory diseases; phagocytosis.

FIGURE 1

The steps of efferocytosis. Efferocytosis is a multi-steps process that involves several steps: finding apoptotic cells, binding apoptotic cells, internalizing and digestion of apoptotic cells. (A) The apoptotic cells release a series of “find me” signals including lysophosphatidylcholine sphingosine-1-phosphate (S1P), uridine diphosphate (UTP) and adenosine triphosphate (ATP), which attract phagocytes to region of apoptotic corpses. These signals are recognized by phagocytes using cognate receptors such as CXCR3, G-protein-coupled receptor (G2A), purinergic receptors (P2Y2), andsphingosine-1-phosphate receptor (S1PRs). (B) The “eat me” signals on the apoptotic cells are sensed by phagocytes, which ingest these dying cells via several receptors and bridging molecules. These crucial signals comprise brain-specific angiogenesis inhibitor 1 (BAI1), T cell immunoglobulin mucin receptor (TIM) 1, TIM3, TIM4, the receptor for advanced glycationend products (RAGE), stabilin-2, phosphatidylserine (PS)-specific bridging molecules, growth arrest specific 6 (Gas6), milk fat globule epidermal growth factor VIII (MFG-E8), and protein S. In addition, calreticulin (CRT) and intercellular adhesion molecule (ICAM) 3 act as the “eat me” signals via interaction with CD14 and low-density lipoprotein-related protein (LRP). (C) Engulfment of apoptotic cells are conducted by phagocytes by recruitment of ingestion receptors along with Rac pathways, the polymerization of actin and rearranging of cytoskeletal. Ingestion receptors can recruit the DOCK180/ELMO1 set [αvβ3, integrin, Tyro3-Ax1-MER proto-oncogene tyrosine kinase (MERTK) (TAM), stabilin-2, and LRP]. D. Healthy cells can resist efferocytosis and leave phagocytes unengulfed via “tolerate me” signals (e.g., CD47, CD31) on the cell surface. SIRPα on the surface of phagocytes can recognize CD47. Similarly, CD31 homodimerizes with CD31 on the phagocytes. Finally, mitochondrial fission and an increase in cytoplasmic calcium occurs in efferocytes. These cellular changes are critical for phagosome sealing. Phagosome fusion with lysosome leads to degradation of apoptotic cells via acid hydrolase activity. The processing of engulfed apoptotic corpses uses microtubule-associated protein light chain 3 (LC3)-dependent phagocytosis and exhibit anti-inflammatory activities.

FIGURE 2

The role of efferocytosis by immune cells in infections. Efferocytosis participates in host defense against invading microbes. However, certain pathogens can escape efferocytosis and accelerate their spread. Efferocytosis is accomplished by professional and unprofessional phagocytes. Remarkably, macrophages and dendritic cells are professional phagocytes that are the most commonly studied of the efferocytes. (A) Ingestion of infected apoptotic cells by macrophages limits secondary necrosis of these cells and bacteria release, thereby improving bacteria clearance. In some cases, certain bacteria can trigger pyroptosis in infected cells. Efferocytotic receptors (i.e., scavenger receptor, complement receptor) are able to recognize pore-induced intracellular traps (PITs) and pytoptotic neutrophil containing bacteria. Subsequently, the process results in bacteria killing via infusion of phagosome to lysosome. However, some pathogens [e.g., methicillin-resistant Staphylococcus aureus (MRSA)] escape efferocytosis through “tolerate me” signal CD47 and signal regulatory protein α (SIRPα) on the infected cells. (B) Recognition and internalization of some viruses [such as herpes simplex virus type 1 (HSV-1)]-infected cells by dendritic cells interact with RAN-binding protein 9 (RANBP9), low-density lipoprotein receptor-related protein 1 (LRP1), and a protein complex comprising AXL. The cross presentation of viral antigen by dendritic cells on MHC class I molecules induces differentiation of CD8⁺ T cells against viruses. Similarly, dendritic cells swallow infected cells and thereby promote expansion of anti-bacteria effector T cells. In the infected cells, pathogen-associated molecular patterns (PAMPs) signal via Toll-like receptors (TLRs) and stimulate production of transforming growth factor-beta (TGF-β) and interleukin (IL)-6, thereby expanding the population of CD4⁺ T cells to T helper (Th)17 cells but inhibiting generation of regulatory T (Treg) cells.

FIGURE 3

The role of efferocytosis in various inflammatory disorders. Efferocytosis is required for tissue homeostasis and organ development. The process is mainly orchestrated by several phagocytes (i.e., microglia, macrophage, dendritic cells). Aberrant efferocytosis has been associated with several inflammatory and autoimmune disorders, including infection, acute lung injury (ALI), asthma, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), diabetes, multiple sclerosis (MS), autoimmune lymphoproliferative syndrome (ALPS) and other inflammatory conditions.