The Role of Efferocytosis in Autoimmune Diseases

Abstract

Apoptosis happens continuously for millions of cells along with the active removal of apoptotic debris in order to maintain tissue homeostasis. In this respect, efferocytosis, i.e., the process of dead cell clearance, is orchestrated through cell exposure of a set of "find me," "eat me," and "tolerate me" signals facilitating the engulfment of dying cells through phagocytosis by macrophages and dendritic cells. The clearance of dead cells via phagocytes is of utmost importance to maintain the immune system tolerance to self-antigens. Accordingly, this biological activity prevents the release of autoantigens by dead cells, thus potentially suppressing the undesirable autoreactivity of immune cells and the appearance of inflammatory autoimmune disorders as systemic lupus erythematous and rheumatoid arthritis. In the present study, the apoptosis pathways and their immune regulation were reviewed. Moreover, efferocytosis process and its impairment in association with some autoimmune diseases were discussed.

Keywords: apoptosis; autoimmune disease; efferocytosis; phagocytosis; systemic lupus erythematous.

Figure 1

Cell death clearance processing by phagocytes through finding apoptotic cells, recognition their signals and engulfment of the cell corpses. (A) The “find me” signal: the dying cells release signals such as UTP, ATP, sphingosine-1-phosphate (S1P), and lysophosphatidylcholine or fractalkine through apoptosis. These “find me” signals can also conduct phagocytes to the location of cell death. Phagocytes can thus sense the “find me” signal to detect apoptotic cells using cognate receptors including sphingosine-1-phosphate receptor (S1PRs), purinergic receptors (P2Y2), G-protein-coupled receptor (G2A), and CXCR3. (B) The “eat me” signal: the dying cells expose “eat me” signals on their surface, so phagocytes can recognize and engulf apoptotic cells by recruiting a complex of receptors and bridging molecules. The main common “eat me” signals include the expression of phosphatidylserine (PS) on the outer layer of plasma membrane, brain-specific angiogenesis inhibitor 1, T cell immunoglobulin mucin receptor (TIM1, TIM3, TIM4), RAGE, and stabilin along with PS-specific bridging molecules, Gas6, Milk Fat Globule EGF Factor 8 (MFG-E8), and protein S. Other “eat me” signals include calreticulin (CRT) and ICAM3, which can modulate the identification and engulfment of apoptotic cells by LRP receptors (via C1q) and CD14, respectively. (C) The engulfment process: after recruitment of engulfment receptors through the activity of Rac pathway, the polymerization of actin and rearranging of cytoskeletal are initiated. Although the mechanism of TIM4 in this process is unknown, some engulfment receptors recruit the DOCK180/ELMO1 set (αvβ3, TAM, stabilin-2, and LRP). Thus, disorders during this step can lead to autoimmunity and inflammatory.

Figure 2

The digestion process of engulfed dead cells. During the engulfment of apoptotic cells, LC3-associated phagocytosis (LAP) pathway accompanied by its components and ULK1/2 complex as a canonical autophagy pathway have specific roles. The class III PI3K collection involving VPS34, Beclin-1, UVRAG, and Rubicon are also important to the localization of PI3P at the LAPosome and canonical autophagy. PI3P has two functions: the employment of the downstream autophagic/LAP machinery including ATG5, ATG7, ATG12, and ATG16L, and fixation of the NOX2 set with recruitment of Rubicon. Also, merging the lysosome and LAPosome maturation is in need of LC3-II. The cholesterol sensors such as liver X receptor, ABCA1, PPARδ, PPARγ, and PGC-1β are similarly required for anti-inflammatory impact of efferocytosis, which can result in producing anti-inflammatory modulator such as IL-10 and TGF-β.