Regulation of Apoptotic Cell Clearance During Resolution of Inflammation

Abstract

Programmed cell death (apoptosis) has an important role in the maintenance of tissue homeostasis as well as the progression and ultimate resolution of inflammation. During apoptosis, the cell undergoes morphological and biochemical changes [e.g., phosphatidylserine (PtdSer) exposure, caspase activation, changes in mitochondrial membrane potential and DNA cleavage] that act to shut down cellular function and mark the cell for phagocytic clearance. Tissue phagocytes bind and internalize apoptotic cells, bodies, and vesicles, providing a mechanism for the safe disposal of apoptotic material. Phagocytic removal of apoptotic cells before they undergo secondary necrosis reduces the potential for bystander damage to adjacent tissue and importantly initiates signaling pathways within the phagocytic cell that act to dampen inflammation. In a pathological context, excessive apoptosis or failure to clear apoptotic material results in secondary necrosis with the release of pro-inflammatory intracellular contents. In this review, we consider some of the mechanisms by which phagocytosis of apoptotic cells can be controlled. We suggest that matching apoptotic cell load with the capacity for apoptotic cell clearance within tissues may be important for therapeutic strategies that target the apoptotic process for treatment of inflammatory disease.

Keywords: apoptosis; inflammation; macrophage; phagocytosis; resolution.

Figure 1

Schematic representation of mechanisms promoting macrophage phagocytosis of AC by lipid mediators. In addition to a role in recognition of N-formylated peptides that are generated during bacterial and mitochondrial protein synthesis, the formyl peptide receptor 2 (ALX/FPR2) also binds to Lipoxin A4, Annexin A1, and Ac2-26 (N-terminal part of Annexin A1) to increase macrophage phagocytosis of AC (Godson et al., 2000; Maderna et al., 2002; Scannell et al., 2007; Maderna et al., 2010). Signaling following ALX/FPR2 binding by these ligands was shown to induce rearrangements in the actin cytoskeleton in a Rho, Rac, and cdc42-dependent manner. GPR32 is thought to be the main receptor for the resolvin D family members 1, 3, and 5 (RvD1,3,5) that acts to promote phagocytosis of AC and reduce NF-κB activity. RvD1 and RvD3 were also found to bind ALX/FPR2 with high affinity and induce macrophage phagocytosis (Arita et al., 2007; Krishnamoorthy et al., 2010, Krishnamoorthy et al., 2012; Dalli et al., 2013b). The resolving E family member 1 (RvE1) increased macrophage phagocytosis of AC via binding to ERV-1/ChemR23. Phosphorylation of Akt and S6 proteins induced cytoskeletal rearrangements as well as promotion of transcription of the anti-inflammatory cytokine IL-10 (Laguna-Fernandez et al., 2018). RvE1 can also competitively bind to the leukotriene B4 receptor BLT4, acting to reduce pro-inflammatory signaling (Arita et al., 2007; Ohira et al., 2010; Laguna-Fernandez et al., 2018). Resolvin D2 (RvD2) mediated activation of GPR18 induced an M2-like macrophage phenotype exhibiting increased phagocytosis via a mechanism involving phosphorylation of the ERK, PKA, and STAT3 (Fredman and Serhan, 2011; Dalli et al., 2013b). Although resolving E2 (RvE2) was also reported to induce macrophage phagocytosis, the pathway that controls this effect has not been clearly identified (Oh et al., 2012).