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导致组织损伤的炎症反应的重要因素。磷脂酰丝氨酸受体(PSR)是一种表达在巨噬细胞、成纤维细胞和上皮细胞上的分子，它与暴露在凋亡细胞上的PS特异结合。然而，一些分子也与巨噬细胞对凋亡细胞的识别和摄取有关。这些分子包括CD14、A类清道夫受体、三磷酸腺苷结合盒转运体1、受体酪氨酸激酶AX1/Mer/Tyro3和α_Vβ_3整合素，它们与CD36结合，与凋亡细胞上一个未知配体识别的凝血酶反应蛋白结合。此外，两个可溶性分子，生长停滞特异基因6产物和乳脂球-EGF-因子8，已被报道与PS结合。因此，虽然体外实验清楚地表明PSR参与了细胞凋亡的抗炎清除，但PSR的生理相关性仍不清楚。为了解决这个问题，我们通过胚胎干细胞中的同源重组产生了PSR缺陷小鼠。PSR^&lt；-/-&gt；小鼠表现出严重的贫血，并在围产期死亡。在PSR^&lt；-/-&gt；胎肝中，红系分化在早期红系细胞阶段受阻。此外，由于T淋巴样细胞发育缺陷，PSR^&lt；-/-&gt；胚胎表现出胸腺萎缩。在PSR^&lt；-/-&gt；胚胎的肝脏和胸腺中，巨噬细胞对凋亡细胞的清除都受到了损害。然而，这并没有诱导炎性细胞因子的上调。这些结果表明，在胚胎发育过程中，PSR对于确定的红细胞生成和T淋巴细胞生成是必需的，与预防炎症反应无关。

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.