**4. Efferocytosis**

The term "efferocytosis" is derived from the Latin word "efferre" meaning "to take to the grave," which describes the process of programmed cell removal (PrCR). In cell biology, efferocytosis is characterized as the swallowing and decomposition of apoptotic cells by phagocytes. The noteworthy point of efferocytosis is that this mechanism includes the production of anti-inflammatory cytokines and the inhibition of pro-inflammatory cytokines. This means that efferocytosis takes place in an immunologically silent state that mechanistically differs from the phagocytosis of pathogens and other opsonized particles [20] in which pro-inflammatory cytokines are produced. Recent evidence has shown that many types of cells have the ability to clear their neighboring dying cells, including both professional and non-professional phagocytes, although it has long been believed that apoptotic cells can only be cleared by efferocytosis by specialized cells. Professional phagocytes include macrophages and immature dendritic cells, while non-professional phagocytes are involved in epithelial cells, endothelial cells, and fibroblasts. The stages in which apoptotic particles are extracted by professional and non-professional phagocytes are the

#### **Figure 1.**

*Recognition of apoptotic cells by phagocytes (The Engulfment Synapse). altered carbohydrate (aCHO),*  β*2-glycoprotein I receptor (*β*2GPIR), brain-specific angiogenesis inhibitor (BAI-1), complement protein C1q (C1q), calreticulin (CRT), growth arrest-specific 6 (Gas6), intercellular adhesion molecule 3 (ICAM-3), Mer tyrosine kynase (MerTK), milk fat globule-EGF factor 8 protein (MFGE8), oxidized low-density lipoprotein (oxLDL), phosphatidyl serin (PtdSer), receptor for advanced glycation end products (RAGE), Src homology 2 domain-bearing protein tyrosine phosphatase substrate-1 (SHPS-1), T-cell immunoglobulin mucin receptor (TIM), thrombospondin-1 (TSB-1).*

same, although various kinetics have been recorded. In fact, the process of efferocytosis is carried out at greater speed and capacity by trained phagocytes [22, 23].

#### **4.1 Find-me signals**

Signals produced by apoptotic cells usually involve two types: soluble molecules and complicated extracellular vesicles. Nucleotides such as adenosine triphosphate (ATP) and uridine triphosphate are among the most widely recognized find-me signals (UTP). In the environment, such nucleotides are released by apoptotic cells through the pannexin-1 channel. They bind purinoreceptor 2 (P2Y2) to the surface of the phagocytes, thus serving as short-range chemo attractants [22–27]. Recent studies have shown that certain mediators of oxidative stress can serve as find-me signals by activating monocyte recruitment towards suffering cells at risk of death. The release of oxidative stress mediators may be a physiological mechanism for the precautionary use of phagocytes before the onset of cell death, but it may also promote the pathogenesis of some conditions [1, 9, 28–31]. Lysophosphatidylcholine (LPC) is a lipid mediator formed and released from apoptotic cells by the calciumindependent isoform of phospholipase A22 (iPLA2). LPC plays a part in the recruitment of macrophages by reacting with the G2 accumulation (G2A) receptor. G2A is a G-protein-coupled (GPCR) receptor that plays a role in the regulation of cell cycles, oncogenesis, immunity, and proliferation. G2A is found in macrophages, dendritic cells, neutrophils, mast cells, T lymphocytes, and B lymphocytes. Although awareness of this receptor has so far been restricted, its most important

#### *Efferocytosis: An Interface between Apoptosis and Pathophysiology DOI: http://dx.doi.org/10.5772/intechopen.97819*

role as an LPC receptor is probably to enable the development of monocyte, neutrophil and lymphocyte recruitment chemo attractants.

Fractalkine (CX3CL1) is a find-me signal which is secreted from apoptotic human B cells in extracellular vesicles. Fractalkine acts as a chemokine which facilitates its recruitment into apoptotic cells by binding to its receptor (CX3CR1) on the surface of the phagocyte 13. Fractalkine also increases the expression of MFGE8, which plays a role as a bridging molecule, in phase 13 of efferocytosis. In addition, apoptotic cells can cause the release of a number of cytokines and chemokines, including MCP-1 and IL-8, involved in the recruitment of monocytes and Tam-Horsfall protein 1 (THP-1) neutrophils, by binding to Fas/CD95 [32].
