New aspects of the C5a receptor

The process of apoptotic cell death for maintenance of cell homeostasis is now believed to be flexible. To examine the mechanism for this flexibility, the process of programmed cell death is sometimes divided into three phases: initiation, effector and execution. We have demonstrated that apoptotic cells commonly express a de novo synthesized C5a receptor (C5aR), which belongs to the G protein-coupled receptor (GPCR) family. A natural agnostic ligand of the C5aR, C5a, is produced from plasma C5 by C5 convertase in the early phase of acute inflammation. Although it is not realistic, we found that C5a can adjust apoptotic cell lifespan long. We recently have read interesting reports that apoptotic cells can release natural agnostic ligands at the initiation phase and corresponding GPCRs are already expressed on cell surfaces of apoptotic cells. Conversely, we found that apoptotic cells commonly release an alternative antagonistic/agnostic ligand of the de novo synthesized C5aR, ribosomal protein S19 (RP S19) polymer. The RP S19 polymer can adjust apoptotic cell lifespan short. Importantly, the C5a-dependent regulation is limited by the C5aR sensitization, but the RP S19 polymer-dependent regulation is unlimited by the C5aR desensitization. Therefore, we suggested that apoptotic cells commonly release agnostic ligands in the initiation phase that should lengthen intermittently a period of the initiation phase. Next, apoptotic cells commonly release antagonistic/agnostic ligands in the effector phase that should continue shortening a period of the effector phase. In addition, we know that an inherited erythroblastopenia is associated with mutations in the RP S19 gene. However, the roles of RP S19 in the formation of erythroblast-macrophage islands are not clearly understood. We recently have found that a different arm that the RP S19 polymer has connects the de novo synthesized C5aR on erythroblasts and the generally expressed C5aR on macrophages. Therefore, we suggested that apoptotic cells commonly release antagonistic/agnostic ligands in the execution phase that should continue connecting apoptotic cells and macrophages in the execution phase for shortening a period of the execution phase. In this review, we introduce new aspects of the C5aR in apoptotic cells and discuss the effects of the long lifespan of apoptotic cell-like neutrophils on the development of periodontitis.