Table 1 The main steps in the efferocytosis process.
From: Phytochemical-mediated efferocytosis and autophagy in inflammation control
Num | Steps | Factors and pathways |
|---|---|---|
1 | -Phagocytes are guided towards ACs by “Find-Me” signals, which act as chemoattractants. -“Find-Me” signals, such as fractalkine, LPC, S1P, and nucleotides (ATP and UTP), play a crucial role in guiding phagocytes toward ACs. -These signals not only guide phagocytes but also enhance their ability to clear ACs and trigger anti-inflammatory responses (detailed in step 5). | |
2 | -Phagocytes distinguish between phagocytic and non-phagocytic cells through the interaction of ACs’ ligands (“Eat-Me” signals) with receptors present in phagocytes. -Different ligands present on the surface of ACs, such as PS, ox-LDL, calreticulin (Calr), ICAM3, C1q, and annexin I, are recognized by engulfment receptors on phagocytes. -Phagocytes can also recognize healthy cells through the “Don’t Eat-Me” signal, which includes CD31, CD47, CD24, PD-L1, and MHC I, to prevent the engulfment of healthy cells. | |
3 | Internalization of ACs [183,184,185,186,187,188,189,190,191,192,193] | -Rac1, a Rho family GTPase, plays a key role in the internalization of ACs during efferocytosis. -Engulfment receptors initiate downstream signaling pathways that trigger Rac1, leading to cytoskeletal rearrangement and engulfment of the target. -Different PS receptors, such as BAI1 and Stabilin-2, have established signaling pathways downstream. -Tim-4 acts as a tethering receptor and promotes efferocytosis by binding ACs on phagocytes, which then use other engulfment receptors, such as integrin, to ingest the ACs. This process is known as two-step engulfment. -Tethering receptors like Tim-4 can promote efferocytosis without interacting with their co-receptors, but they may have biochemical interactions with co-receptors, such as Mertk. |
4 | Degradation of ACs [44, 97, 194,195,196,197,198,199,200,201,202] | Phagocytosis degrades ACs by creating phagosomes that become more acidic and eventually join with lysosomes for AC collapse. -LAP accelerates the process by maturing phagosomes more efficiently, leading to faster AC degradation. -Phagocytes experience a doubling of intracellular contents during efferocytosis, leading to the release of some contents and adjustments in metabolism to maintain appropriate levels. -Engulfment receptors recognizing PS and AC-derived sterols activate LXR and PPAR, resulting in altered energy metabolism and cholesterol efflux. -Alterations in energy metabolism impact the body’s ability to fight inflammation by promoting the generation of anti-inflammatory cytokines and altering glucose transport and lactate release during efferocytosis. |
5 | -Efferocytosis is associated with an anti-inflammatory response that involves the production of anti-inflammatory cytokines (IL-10 & TGF-β) and the suppression of pro-inflammatory cytokines (TNF-α & IL-1β). -Nuclear receptors (e.g., LXR & PPAR) are activated by binding to AC-derived ligands, leading to the upregulation of genes involved in efferocytosis and anti-inflammatory responses (e.g., lipid metabolism & anti-inflammatory responses). |
