Role of the phosphatidylserine receptor in development of hematopoietic cells

磷脂酰丝氨酸受体在造血细胞发育中的作用

• 批准号: 16390144
• 负责人: FUKUI Yoshinori
• 金额: $ 9.54万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390144/
• 关键词: phosphatidylserine receptor; apoptotic cells; phagocytosis; anemima; T cell development; ホスファチジルセリン受容体; 赤血球分化; T細胞分化; ノックアウトマウス

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.

巨噬细胞清除凋亡细胞被认为对于预防导致组织损伤的炎症反应很重要。磷脂酰丝氨酸受体 (PSR) 已被确定为在巨噬细胞、成纤维细胞和上皮细胞上表达的分子，它与凋亡细胞上暴露的 PS 特异性结合。然而，一些分子也与巨噬细胞识别和摄取凋亡细胞有关。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 和 α_Vβ_3 整联蛋白，该整联蛋白与 CD36 结合，与凋亡细胞上未定义配体识别的血小板反应蛋白结合。此外，据报道，两种可溶性分子，即生长停滞特异性基因 6 产物和乳脂肪球 -EGF -因子 8，可与 PS 结合。因此，尽管体外实验清楚地表明PSR参与凋亡细胞的抗炎清除，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 (ES) 细胞中的同源重组产生了 PSR 缺陷小鼠。 PSR^</->小鼠表现出严重贫血并在围产期死亡。在PSR^</->胎儿肝脏中，红细胞分化在早期成红细胞阶段被阻断。此外，PSR^-/-胚胎由于T淋巴细胞的发育缺陷而表现出胸腺萎缩。 PSR^-/-胚胎的肝脏和胸腺中巨噬细胞对凋亡细胞的清除均受到损害。然而，这并没有引起炎症细胞因子的上调。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，与炎症反应的预防无关。

项目成果

DOCK2 is required in T cell precursors for development of Vα14 natural killar T (NKT) cells

DOCK2 在 T 细胞前体中是 Vα14 自然杀伤 T (NKT) 细胞发育所必需的

• 发表时间: 2006
• 期刊: J.Immunol. (in press)
• 作者: Elsi Dwi Hapsari;Yuria Mantani;Hiroya Matsuo;Kunisaki Y. et al.
• 通讯作者: Kunisaki Y. et al.

Deletion of DOCK2, a regulator of the actin cytoskeleton in lymphocytes, suppresses cardiac allograft rejection

• DOI: 10.1084/jem.20050911
• 发表时间: 2005-10-17
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Jiang, HS;Erickson, LM;Fukui, Y
• 通讯作者: Fukui, Y

免疫シナプス形成を制御するCDMファミリー分子DOCK2

DOCK2，一种控制免疫突触形成的 CDM 家族分子

• 发表时间: 2004
• 期刊: Molecular Medicine 41 (増刊「免疫2005」)
• 作者: 岡崎 拓;本庶 佑;周岡 拓;Nombela-Arrieta C et al.;Handa Y et al.;Nombela-Arrieta C et al.;Handa Y et al.;Nombela-Arrieta C et al.;Handa Y et al.;Gercia-Bernal D et al.;Kunisaki Y et al.;Shulman Z et al.;Kunisaki Y et al.;福井宣規;Garcia-Bernal D et al.;Shulman Z et al.;Kunisaki Y et al.;Fukui Y.;Garcia-Bernal D et al.;Kunisaki Y et al.;Kunisaki Y et al.;Jiang H et al.;福井宣規;Fukui Y.;Jiang H et al.;Nombela-Arrieta C et al.;Kunisaki Y et al.;福井宣規
• 通讯作者: 福井宣規