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Angiostatin inhibits activation and migration of neutrophils

机译：血管生成抑制素抑制中性粒细胞的活化和迁移

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There is a critical need to identify molecules that modulate the biology of neutrophils because activated neutrophils, though necessary for host defense, cause exuberant tissue damage through production of reactive oxygen species and increased lifespan. Angiostatin, an endogenous anti-angiogenic cleavage product of plasminogen, binds to integrin αvβ3, ATP synthase and angiomotin and its expression is increased in inflammatory conditions. We test the hypothesis that angiostatin inhibits neutrophil activation, induces apoptosis and blocks recruitment in vivo and in vitro. The data show immuno-reactivity for plasminogen/angiostatin in resting neutrophils. Angiostatin conjugated to FITC revealed that angiostatin was endocytozed by activated mouse and human neutrophils in a lipid raft-dependent fashion. Co-immunoprecipitation of human neutrophil lysates, confocal microscopy of isolated mouse and human neutrophils and functional blocking experiments showed that angiostatin complexes with flotillin-1 along with integrin αvβ3 and ATP synthase. Angiostatin inhibited fMLP-induced neutrophil polarization, as well as caused inhibition of hsp-27 phosphorylation and stabilization of microtubules. Angiostatin treatment, before or after LPS-induced neutrophil activation, inhibited phosphorylation of p38 and p44/42 MAPKs, abolished reactive oxygen species production and released the neutrophils from suppressed apoptosis, as indicated by expression of activated caspase-3 and morphological evidence of apoptosis. Finally, intravital microscopy and myeloperoxidase assay showed inhibition of neutrophil recruitment in post-capillary venules of TNFα-treated cremaster muscle in mouse. These in vitro and in vivo data demonstrate angiostatin as a broad deactivator and silencer of neutrophils and an inhibitor of their migration. These data potentially open new avenues for the development of anti-inflammatory drugs.
机译：迫切需要鉴定可调节嗜中性粒细胞生物学的分子，因为活化的嗜中性粒细胞尽管对宿主防御具有必要作用，但通过产生活性氧物种和延长寿命而引起旺盛的组织损伤。纤溶酶原的内源性抗血管生成裂解产物血管抑素与整联蛋白αvβ3，ATP合酶和血管动蛋白结合，在炎症条件下其表达增加。我们测试血管生成抑制素抑制中性粒细胞活化，诱导细胞凋亡并阻止体内和体外募集的假说。数据显示静止中性粒细胞中纤溶酶原/血管抑制素的免疫反应性。缀合到FITC的血管抑制素显示血管抑制素被脂筏依赖性的激活的小鼠和人类嗜中性粒细胞吞噬。人嗜中性粒细胞裂解物的共免疫沉淀，分离的小鼠和人类嗜中性粒细胞的共聚焦显微镜及功能阻断实验表明，血管抑素与flotillin-1以及整联蛋白αvβ3和ATP合酶复合。血管生成抑制素抑制fMLP诱导的嗜中性白细胞极化，并抑制hsp-27磷酸化并稳定微管。 LPS诱导的中性粒细胞活化之前或之后，血管抑素治疗可抑制p38和p44 / 42 MAPKs的磷酸化，消除活性氧的产生，并从抑制的凋亡中释放中性粒细胞，这由活化的caspase-3的表达和凋亡的形态学证据表明。最后，活体显微镜检查和髓过氧化物酶检测显示，在小鼠中，TNFα处理的提睾肌的毛细血管后小静脉中性粒细胞募集受到抑制。这些体外和体内数据证明血管抑制素是嗜中性粒细胞的广泛的失活剂和沉默剂以及它们的迁移的抑制剂。这些数据潜在地为抗炎药的开发开辟了新途径。

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