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ORAI1 and ORAI2 modulate murine neutrophil calcium signaling, cellular activation, and host defense.
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2020-09-29 , DOI: 10.1073/pnas.2008032117
Derayvia Grimes 1 , Ryan Johnson 1 , Madeline Pashos 1 , Celeste Cummings 1 , Chen Kang 2 , Georgia R Sampedro 1 , Eric Tycksen 3 , Helen J McBride 4 , Rajan Sah 2 , Clifford A Lowell 5 , Regina A Clemens 6
Affiliation  

Calcium signals are initiated in immune cells by the process of store-operated calcium entry (SOCE), where receptor activation triggers transient calcium release from the endoplasmic reticulum, followed by opening of plasma-membrane calcium-release activated calcium (CRAC) channels. ORAI1, ORAI2, and ORAI3 are known to comprise the CRAC channel; however, the contributions of individual isoforms to neutrophil function are not well understood. Here, we show that loss of ORAI1 partially decreases calcium influx, while loss of both ORAI1 and ORAI2 completely abolishes SOCE. In other immune-cell types, loss of ORAI2 enhances SOCE. In contrast, we find that ORAI2-deficient neutrophils display decreased calcium influx, which is correlated with measurable differences in the regulation of neutrophil membrane potential via KCa3.1. Decreased SOCE in ORAI1-, ORAI2-, and ORAI1/2-deficient neutrophils impairs multiple neutrophil functions, including phagocytosis, degranulation, leukotriene, and reactive oxygen species (ROS) production, rendering ORAI1/2-deficient mice highly susceptible to staphylococcal infection. This study demonstrates that ORAI1 and ORAI2 are the primary components of the neutrophil CRAC channel and identifies subpopulations of neutrophils where cell-membrane potential functions as a rheostat to modulate the SOCE response. These findings have implications for mechanisms that modulate neutrophil function during infection, acute and chronic inflammatory conditions, and cancer.



中文翻译:

ORAI1 和 ORAI2 调节鼠中性粒细胞钙信号传导、细胞活化和宿主防御。

钙信号通过储存操作的钙进入 (SOCE) 过程在免疫细胞中启动,其中受体激活触发内质网瞬时钙释放,然后打开质膜钙释放活化钙 (CRAC) 通道。已知 ORAI1、ORAI2 和 ORAI3 构成 CRAC 通道;然而,个别亚型对中性粒细胞功能的贡献尚不清楚。在这里,我们表明 ORAI1 的缺失部分减少了钙的流入,而 ORAI1 和 ORAI2 的缺失则完全消除了 SOCE。在其他免疫细胞类型中,ORAI2 的缺失会增强 SOCE。相比之下,我们发现 ORAI2 缺陷的中性粒细胞显示钙内流减少,这与通过 KCa3.1 调节中性粒细胞膜电位的可测量差异相关。ORAI1-中的 SOCE 降低,ORAI2 和 ORAI1/2 缺陷的中性粒细胞会损害多种中性粒细胞功能,包括吞噬作用、脱粒、白三烯和活性氧 (ROS) 的产生,从而使 ORAI1/2 缺陷的小鼠对葡萄球菌感染高度敏感。该研究表明,ORAI1 和 ORAI2 是中性粒细胞 CRAC 通道的主要成分,并确定了细胞膜电位作为变阻器调节 SOCE 反应的中性粒细胞亚群。这些发现对在感染、急性和慢性炎症状况以及癌症期间调节中性粒细胞功能的机制具有重要意义。使 ORAI1/2 缺陷小鼠对葡萄球菌感染高度敏感。该研究表明,ORAI1 和 ORAI2 是中性粒细胞 CRAC 通道的主要成分,并确定了细胞膜电位作为变阻器调节 SOCE 反应的中性粒细胞亚群。这些发现对在感染、急性和慢性炎症状况以及癌症期间调节中性粒细胞功能的机制具有重要意义。使 ORAI1/2 缺陷小鼠对葡萄球菌感染高度敏感。该研究表明,ORAI1 和 ORAI2 是中性粒细胞 CRAC 通道的主要成分,并确定了细胞膜电位作为变阻器调节 SOCE 反应的中性粒细胞亚群。这些发现对在感染、急性和慢性炎症状况以及癌症期间调节中性粒细胞功能的机制具有重要意义。

更新日期:2020-09-30
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