Lim Hye Min, Woon Heo, Han Jung Woo, Baba Yoshihiro, Kurosaki Tomohiro, Lee Min Goo, Kim Joo Young
Department of Pharmacology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka 565-0871, Japan; Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Mediators Inflamm. 2017;2017:8158514. doi: 10.1155/2017/8158514. Epub 2017 Feb 15.
STIM1 is the only currently known intracellular calcium sensor that functions as the calcium influx regulator controlling immune cell activation. STIM1 function in immune cell calcium signalling has been studied extensively; however, its role in microglia, innate immune cells in brain, has not been fully understood. Here, we report that murine microglia lost store-operated calcium influx and displayed aberrant immunological functions. Microglial functions regulated by chronic and global [Ca] changes were reduced significantly, including cytokine releases and opsonin-dependent phagocytosis. More dramatically, cellular functions governed by Ca regulation in local microdomains at the cell periphery, such as UDP-induced phagocytosis and ATP-stimulated chemotactic migration, were severely reduced in microglia. Interestingly, UDP-induced Orai1 mobilization to the peripheral region was greatly attenuated in microglia. Their chemotactic migration defect was reproduced in vivo in embryonic brain; the aggregated number of microglia in LPS- (lipopolysaccharide-) injected lesions was much smaller than that in wild-type microglia. Furthermore, the neuron phagoptosis activities of activated microglia were significantly diminished in the microglia. These in vitro and in vivo results suggest that STIM1-mediated store-operated calcium entry is important for the regulation of global [Ca] changes which differentiates into active immune state of microglia, but it is more crucial for the regulation of local [Ca] microdomains which mediates the acute motility of murine microglia.
基质相互作用分子1（STIM1）是目前已知的唯一一种细胞内钙传感器，作为钙内流调节器控制免疫细胞的激活。STIM1在免疫细胞钙信号传导中的功能已得到广泛研究；然而，其在小胶质细胞（大脑中的固有免疫细胞）中的作用尚未完全明确。在此，我们报告小鼠小胶质细胞失去了储存式钙内流，并表现出异常的免疫功能。由慢性和全局性[Ca]变化调节的小胶质细胞功能显著降低，包括细胞因子释放和调理素依赖性吞噬作用。更显著的是，小胶质细胞中由细胞周边局部微区的Ca调节所控制的细胞功能，如UDP诱导的吞噬作用和ATP刺激的趋化性迁移，严重降低。有趣的是，UDP诱导的Orai1向周边区域的动员在小胶质细胞中大大减弱。它们的趋化性迁移缺陷在胚胎大脑中得以在体内重现；注射脂多糖（LPS）的损伤部位聚集的小胶质细胞数量比野生型小胶质细胞中的要少得多。此外，活化小胶质细胞的神经元吞噬凋亡活性在基质相互作用分子1缺陷的小胶质细胞中显著降低。这些体外和体内结果表明，STIM1介导的储存式钙内流对于调节全局性[Ca]变化很重要，这种变化可使小胶质细胞分化为活跃的免疫状态，但对于介导小鼠小胶质细胞急性运动性的局部[Ca]微区的调节更为关键。
