High molecular weight kininogen binds phosphatidylserine and opsonizes urokinase plasminogen activator receptor-mediated efferocytosis.
High molecular weight kininogen binds phosphatidylserine and opsonizes urokinase plasminogen activator receptor-mediated efferocytosis.
复制标题
DOI：
10.4049/jimmunol.1302590
复制
发表时间：
2014-05-01
期刊：
影响因子：
--
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Yang A;Dai J;Xie Z;Colman RW;Wu Q;Birge RB;Wu Y
凋亡细胞的吞噬作用（吞噬作用）对于调节免疫应答和组织稳态是必不可少的，并且由吞噬受体介导。本研究发现尿激酶型纤溶酶原激活物受体（uPAR）在凋亡细胞的内化过程中起重要作用，并探讨了其作用机制。在基于流式细胞术的吞噬试验中，uPAR缺陷型（uPAR−/−）巨噬细胞在凋亡细胞的内化方面显示出显著缺陷，但未显示出系留。当用凋亡细胞攻击uPAR−/−小鼠时，它们表现出明显的脾肿大，这是由于大量凋亡细胞在脾脏中积聚所致。在HEK-293细胞中，uPAR的过表达可增强细胞的吞噬功能，而膜联蛋白V和磷脂酰丝氨酸（PS）脂质体可抑制这种作用，提示uPAR介导的细胞吞噬功能依赖于PS。在血清缺乏高分子量激肽原（HK），uPAR配体，uPAR介导的红细胞增多症显着减弱，这是拯救补充HK。流式细胞仪检测发现，HK选择性结合凋亡细胞，而不是活细胞。在纯化体系中，HK与PS脂质体特异性结合。HK与凋亡细胞的结合诱导其快速裂解为双链HKa和缓激肽。HKa的重链和轻链均与PS脂质体和凋亡细胞相关。HKa与uPAR的结合亲和力高于HK。过表达Rac 1/N17 cDNA可抑制uPAR介导的细胞增殖。HK + PS脂质体可刺激uPAR-293细胞中CrkII与p130 Cas和Dock-180形成复合物，并激活Rac 1，但对对照HEK-293细胞无此作用。因此，uPAR通过HK与凋亡细胞上的PS相互作用和Rac 1通路的激活介导了细胞凋亡。
Phagocytosis of apoptotic cells (efferocytosis) is essential for regulation of immune responses and tissue homeostasis, and is mediated by phagocytic receptors. In this study we found that urokinase plasminogen activator receptor (uPAR) plays an important role in internalization of apoptotic cells, and also characterized the underlying mechanisms. In a flow cytometry-based phagocytic assay, uPAR-deficient (uPAR−/−) macrophages displayed significant defect in internalization but not tethering of apoptotic cells. When uPAR−/− mice were challenged with apoptotic cells, they exhibited pronounced splenomegaly resulting from accumulation of abundant apoptotic cells in spleen. Overexpression of uPAR in HEK-293 cells enhanced efferocytosis, which was inhibited by annexin V and phosphatidylserine (PS) liposome, suggesting that uPAR-mediated efferocytosis is dependent on PS. In serum lacking high-molecular-weight kininogen (HK), a uPAR ligand, uPAR-mediated efferocytosis was significantly attenuated, which was rescued by replenishment of HK. As detected by flow cytometry, HK selectively bound to apoptotic cells, but not viable cells. In purified systems, HK was specifically associated with PS liposome. HK binding to apoptotic cells induced its rapid cleavage to two-chain HKa and bradykinin. Both heavy chain and light chain of HKa were associated with PS liposome and apoptotic cells. HKa has higher binding affinity than HK to uPAR. Overexpression of Rac1/N17 cDNA inhibited uPAR-mediated efferocytosis. HK plus PS liposome stimulated a complex formation of CrkII with p130Cas and Dock-180, and Rac1 activation in uPAR-293 cells, but not in control HEK-293 cells. Thus, uPAR mediates efferocytosis through HK interaction with PS on apoptotic cells and activation of Rac1 pathway.
登录
查看更多内容
DOI：
10.1152/ajpheart.1998.275.1.h145
发表时间：
1998-07-01
影响因子：
4.8
作者：
Khan, MMH;Kunapuli, SP;Colman, RW
通讯作者：
Colman, RW
影响因子：
30.5
作者：
Anderson, HA;Maylock, CA;Shacter, E
通讯作者：
Shacter, E
影响因子：
5.6
作者：
Barbasz, Anna;Guevara-Lora, Ibeth;Kozik, Andrzej
通讯作者：
Kozik, Andrzej
DOI：
10.1161/01.atv.0000240290.70852.c0
发表时间：
2006-10-01
影响因子：
8.7
作者：
Khan, Mohammad M.;Bradford, Harlan N.;Colman, Robert W.
通讯作者：
Colman, Robert W.
影响因子：
15.9
作者：
Colman, RW;Pixley, RA;McCrae, KR
通讯作者：
McCrae, KR