Impaired clearance of apoptotic cells in chronic inflammatory diseases: therapeutic implications

Abstract

In healthy individuals, billions of cells die by apoptosis every day. Removal of the dead cells by phagocytosis (a process called efferocytosis) must be efficient to prevent secondary necrosis and the consequent release of pro-inflammatory cell contents that damages the tissue environment and provokes autoimmunity. In addition, detection and removal of apoptotic cells generally induces an anti-inflammatory response. As a consequence improper clearance of apoptotic cells, being the result of either genetic anomalies and/or a persistent disease state, contributes to the establishment and progression of a number of human chronic inflammatory diseases such as autoimmune and neurological disorders, inflammatory lung diseases, obesity, type 2 diabetes, or atherosclerosis. During the past decade, our knowledge about the mechanism of efferocytosis has significantly increased, providing therapeutic targets through which impaired phagocytosis of apoptotic cells and the consequent inflammation could be influenced in these diseases.

Keywords: apoptotic cell; atherosclerosis; autoimmunity; inflammation; obesity; phagocytosis; therapy; type 2 diabetes.

Figure 1

Mechanism of apoptotic cell clearance. For initiating phagocytosis apoptotic cells release “find me” signals for the phagocytes. After finding the recognition of apoptotic cells by phagocyte receptors is mediated by the display of “eat me” signals (e.g., PS and ACAMPs) and the disappearance of the so-called “do not eat me” signals (e.g., CD31 and CD47) on the apoptotic cell surface. Among others, these receptors include the PS receptors (Tim4, stabilin-2, and BAI1) and receptors such as MerTk, SCARF1, CD36, and integrin αvβ5 together with TG2 recognizing apoptotic cells through bridging molecules (e.g., TSP-1, C1q, Gas6, MFG-E8, and protein S). Binding of apoptotic cells to the phagocytic receptors triggers two evolutionary conserved signaling pathways. MerTk, BAI1, and αvβ3/5 receptors will activate the DOCK180/CrkII/ELMO complex, while CD91/LPR1 and stabilin-2 will activate the adaptor protein GULP. Both pathways converge on the small GTPase Rac, which initiates actin rearrangement and phagocytosis. Following engulfment, apoptotic cell derived lipids (oxysterols and fatty acids) trigger the lipid-sensing LXR and PPAR receptors leading to enhanced retinoid production. Retinoid receptors together with LXR and PPARs upregulate a number of phagocytic receptors to further enhance the engulfing capacity of macrophages under conditions when the rate of apoptosis is increased.