Cross-Talk between Shp1 and PIPKIγ Controls Leukocyte Recruitment.
Cross-Talk between Shp1 and PIPKIγ Controls Leukocyte Recruitment.
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DOI：
10.4049/jimmunol.1500606
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发表时间：
2015-08-01
期刊：
影响因子：
--
通讯作者：
Zarbock A
中科院分区：
文献类型：
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作者：
Stadtmann A;Block H;Volmering S;Abram C;Sohlbach C;Boras M;Lowell CA;Zarbock A
中性粒细胞募集到炎症部位在宿主防御中起着关键作用。然而，由于细胞因子、氧化剂和蛋白酶的释放，中性粒细胞在组织中的过度激活和积聚可能会导致组织损伤和自身免疫。急性炎症中的中性粒细胞黏附是由黏附分子L黏附分子-1(αSelectinβ2，LFA-1)激活引起的，黏附黏附可通过E-选择素滚动(缓慢)或暴露于趋化因子CXCL1(快速)而诱导。尽管具有重要的临床意义，但对整合素黏附和中性粒细胞募集的负性调节的细胞内在分子机制知之甚少。缺乏酪氨酸磷酸酶SHP1的小鼠表现出白细胞粘附性增加，但这些数据的解释受到这些小鼠严重的全球表型的限制。在这里，我们使用SHP1全局和髓系限制性缺失的小鼠来研究体外和体内中性粒细胞的抑制、黏附、爬行和跨内皮细胞迁移。SHP1缺乏会导致体内中性粒细胞黏附增加。然而，在这些小鼠中，中性粒细胞的爬行、移行和趋化能力都降低了。在机制上，SHP1结合并控制PIPKI的γ活性，从而调节PtdIns(4，5)P2水平和黏附。因此，SHP1参与了整合素的失活和中性粒细胞重新募集到炎症组织的调节。
Neutrophil recruitment to site of inflammation plays a pivotal role in host defense. However, an overwhelming activation and accumulation of neutrophils in the tissue may cause tissue damage and autoimmunity due to release of cytokines, oxidants, and proteases. Neutrophil adhesion in acute inflammation is initiated by activation of αLβ2 (LFA-1), which can be induced by rolling on E-selectin (slowly) or by exposure to the chemokine CXCL1 (rapidly). Despite the clinical importance, cell-intrinsic molecular mechanisms of negative regulation of integrin adhesiveness and neutrophil recruitment are poorly understood. Mice deficient in the tyrosine phosphatase Shp1 show increased leukocyte adhesion, but interpretation of these data is limited by the severe global phenotype of these mice. Here, we used mice with global and myeloid-restricted deletion of Shp1 to study neutrophil arrest, adhesion, crawling and transendothelial migration in vitro and in vivo. Shp1 deficiency results in an increased neutrophil adhesion in vivo. However, neutrophil crawling, transmigration and chemotaxis were reduced in these mice. Mechanistically, Shp1 binds and controls PIPKIγ-activity and thereby modulates PtdIns(4,5)P2 levels and adhesion. Thus, Shp1 is involved in the deactivation of integrins and regulation of neutrophil recruitment into inflamed tissue.