Cellular Responses to the Efferocytosis of Apoptotic Cells

Abstract

The rapid and efficient phagocytic clearance of apoptotic cells, termed efferocytosis, is a critical mechanism in the maintenance of tissue homeostasis. Removal of apoptotic cells through efferocytosis prevents secondary necrosis and the resultant inflammation caused by the release of intracellular contents. The importance of efferocytosis in homeostasis is underscored by the large number of inflammatory and autoimmune disorders, including atherosclerosis and systemic lupus erythematosus, that are characterized by defective apoptotic cell clearance. Although mechanistically similar to the phagocytic clearance of pathogens, efferocytosis differs from phagocytosis in that it is immunologically silent and induces a tissue repair response. Efferocytes face unique challenges resulting from the internalization of apoptotic cells, including degradation of the apoptotic cell, dealing with the extra metabolic load imposed by the processing of apoptotic cell contents, and the coordination of an anti-inflammatory, pro-tissue repair response. This review will discuss recent advances in our understanding of the cellular response to apoptotic cell uptake, including trafficking of apoptotic cell cargo and antigen presentation, signaling and transcriptional events initiated by efferocytosis, the coordination of an anti-inflammatory response and tissue repair, unique cellular metabolic responses and the role of efferocytosis in host defense. A better understanding of how efferocytic cells respond to apoptotic cell uptake will be critical in unraveling the complex connections between apoptotic cell removal and inflammation resolution and maintenance of tissue homeostasis.

Keywords: cellular metabolism; efferocytosis; host defense; inflammation resolution; intracellular trafficking; transcriptional regulation.

Figure 1

Efferosome Maturation Pathways. Efferocytosis can occur through the canonical endo-lysosomal maturation pathway (left) in which the GTPases Rab5 and Rab7 mediate the sequential fusion of early endosomes (EE), late endosomes (LE), and lysosomes (LY) with the maturing efferosome. Unlike phagocytosis, this efferosome maturation pathway also involves Rab17 which directs the degraded contents from the efferosome to the recycling endosome from where they may be exocytosed, thereby avoiding the delivery of these materials to antigen loading compartments. In addition to the canonical pathway, some efferosomes may mature through an LC3-mediated, autophagy-like pathway (right). In this pathway, the efferosome recruits the protein LC3 which then mediates a rapid degradation of the efferosome in a fashion which suppresses antigen presentation. Similar to LC3-associated phagocytosis, the recruitment of the autophagy-related proteins ATG5 and ATG7, as well as Rubicon to the nascent efferosome appear to be important for efferocytosis through this pathway. The activity of ATG5 and ATG7 are inhibited by Rab35a, which is activated downstream of TLR signaling. Figure produced using BioRender.

Figure 2

Efferocyte Metabolism. The biomolecules released as efferocytosed apoptotic cells are degraded must be processed by the efferocyte, incurring a significant metabolic load. Cholesterol (C) is exported from the efferosome to cytosolic carriers which, in the presence of cholesterol transporters such as pABCA1 and ABCG1, can export this cholesterol to circulating high density lipoprotein. In the absence of sufficient export, cholesterol is esterified into cholesterol esters (CE) which can accumulate in the endoplasmic reticulum (ER). DNA is degraded in the efferosome by DNase II, and proteins by a range of cathepsin and other proteases, with the resulting nucleotides and amino acids transported into the cytosol where they are recycled. The amino acid arginine is converted in the cytosol to the putrescine, which activates Dbl to enhance Rac1 activity, thereby promoting the efferocytosis of additional apoptotic cells. Lastly, the activation or PPAR and LXR nuclear receptors by lipid-derived metabolites induces a pro-efferocytic metabolic profile via upregulation of cholesterol export machinery and upregulation of lipid β-oxidation. Figure prepared in BioRender.