Sogkas Georgios, Vögtle Timo, Rau Eduard, Gewecke Britta, Stegner David, Schmidt Reinhold E, Nieswandt Bernhard, Gessner J Engelbert
Clinical Department of Immunology and Rheumatology, Hannover Medical School, Germany.
Chair of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Germany.
Eur J Immunol. 2015 Jul;45(7):2143-53. doi: 10.1002/eji.201445337. Epub 2015 May 15.
Stromal interaction molecule 1 (STIM1)-dependent store operated calcium-entry (SOCE) through Orai1-mediated calcium (Ca(2+) ) influx is considered a major pathway of Ca(2+) signaling, serving T-cell, mast cell, and platelet responses. Here, we show that Orai1 is critical for neutrophil function. Orai1-deficient neutrophils present defects in fMLP and complement C5a-induced Ca(2+) influx and migration, although they respond normally to another chemoattractant, CXCL2. Up until now, no specific contribution of Orai1 independent from STIM1 or SOCE has been recognized in immune cells. Here, we observe that Orai1-deficient neutrophils exhibit normal STIM1-dependent SOCE and STIM1-deficient neutrophils respond to fMLP and C5a efficiently. Despite substantial cytokine production, Orai1(-/-) chimeric mice show impaired neutrophil recruitment in LPS-induced peritonitis. Moreover, Orai1 deficiency results in profoundly defective C5a-triggered neutrophil lung recruitment in hypersensitivity pneumonitis. Comparative evaluation of inflammation in Stim1(-/-) chimeras reveals a distinct pathogenic contribution of STIM1, including its involvement in IgG-induced C5a production. Our data establish Orai1 as key signal mediator of C5aR activation, contributing to inflammation by a STIM1-independent pathway of Ca(2+) -influx in neutrophils.
基质相互作用分子1（STIM1）依赖的经Orai1介导的钙内流的钙库操纵性钙内流（SOCE）被认为是钙信号传导的主要途径，参与T细胞、肥大细胞和血小板反应。在此，我们表明Orai1对中性粒细胞功能至关重要。缺乏Orai1的中性粒细胞在fMLP和补体C5a诱导的钙内流及迁移方面存在缺陷，尽管它们对另一种趋化因子CXCL2反应正常。到目前为止，在免疫细胞中尚未认识到Orai1独立于STIM1或SOCE的特定作用。在此，我们观察到缺乏Orai1的中性粒细胞表现出正常的STIM1依赖的SOCE，而缺乏STIM1的中性粒细胞对fMLP和C5a反应有效。尽管细胞因子产生大量，但Orai1基因敲除嵌合小鼠在脂多糖诱导的腹膜炎中中性粒细胞募集受损。此外，Orai1缺乏导致超敏性肺炎中C5a触发的中性粒细胞肺募集严重缺陷。对Stim1基因敲除嵌合体炎症的比较评估揭示了STIM1的独特致病作用，包括其参与IgG诱导的C5a产生。我们的数据确定Orai1是C5aR激活的关键信号介质，通过中性粒细胞中不依赖STIM1的钙内流途径促进炎症反应。
