Role of the phosphatidylserine receptor in development of hematopoietic cells

巨噬细胞清除凋亡细胞被认为是预防炎症反应导致组织损伤的重要因素。磷脂酰丝氨酸受体（phosphatidylserine receptor， PSR）是巨噬细胞、成纤维细胞和上皮细胞上表达的一种分子，它特异性地与暴露在凋亡细胞上的PS结合。然而，一些分子也参与巨噬细胞对凋亡细胞的识别和摄取。这些包括细胞表面分子，如CD14， A类清道夫受体，ATP结合盒转运蛋白1，受体酪氨酸激酶Ax1/Mer/Tyro3， α_Vβ_3整合素，与CD36结合，与凋亡细胞上的一种未定义配体识别的血栓反应蛋白结合。此外，两种可溶性分子，生长抑制特异性基因6产物和乳脂球- egf -因子8，已被报道与PS结合。因此，尽管体外实验明确表明PSR参与细胞凋亡的抗炎清除，但其生理相关性尚不清楚。为了解决这个问题，我们在胚胎干细胞（ES）中通过同源重组产生psr缺陷小鼠。PSR^<-/->小鼠表现出严重的贫血，并在围产期死亡。在PSR^<-/->胎肝中，红细胞分化在早期红母细胞阶段被阻断。此外，PSR^<-/->胚胎由于t淋巴样细胞发育缺陷而表现出胸腺萎缩。巨噬细胞对凋亡细胞的清除在PSR^<-/->胚胎的肝脏和胸腺均受到损害。然而，这并没有诱导炎症细胞因子的上调。这些结果表明，在胚胎发育过程中，PSR是最终的红细胞生成和t淋巴生成所必需的，独立于炎症反应的预防。

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.