Role of the phosphatidylserine receptor in development of hematopoietic cells

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Clearance of apoptotic cells by macrophages is considered important for prevention of inflammatory responses leading to tissue damage. The phosphatidylserine receptor (PSR) has been identified as a molecule expressed on macrophages, fibroblasts and epithelial cells, which specifically binds to PS exposed on apoptotic cells. However, several molecules have been also implicated in the recognition and ingestion of apoptotic cells by macrophages. These include cell-surface molecules such as CD14,class A scavenger receptor, ATP binding cassette transporter 1,receptor tyrosine kinase Ax1/Mer/Tyro3,and α_Vβ_3 integrin which, in association with CD36,binds to thrombospondin recognized by an undefined ligand on apoptotic cells. In addition, two soluble molecules, growth arrest-specific gene 6 product and milk fat globule-EGF-factor 8,have been reported to bind to PS. Therefore, although in vitro experiments clearly indicate that PSR is involved in anti-inflammatory clearance of cells undergoing apoptosis, the physiological relevance of PSR remains unclear. To address this issue, we generated PSR-deficient mice by homologous recombination in embryonic stem (ES) cells. PSR^<-/-> mice exhibited severe anemia and died during the perinatal period. In the PSR^<-/-> fetal livers, erythroid differentiation was blocked at an early erythroblast stage. In addition, PSR^<-/-> embryos exhibited thymus atrophy owing to a developmental defect of T-lymphoid cells. Clearance of apoptotic cells by macrophages was impaired in both liver and thymus of PSR^<-/-> embryos. However, this did not induce up-regulation of inflammatory cytokines. These results indicate that during embryonic development, PSR is required for definitive erythropoiesis and T-lymphopoiesis, independently of the prevention of inflammatory responses.