Abstract
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 STIM1−/− murine microglia lost store-operated calcium influx and displayed aberrant immunological functions. Microglial functions regulated by chronic and global [Ca2+]i changes were reduced significantly, including cytokine releases and opsonin-dependent phagocytosis. More dramatically, cellular functions governed by Ca2+ regulation in local microdomains at the cell periphery, such as UDP-induced phagocytosis and ATP-stimulated chemotactic migration, were severely reduced in STIM1−/− microglia. Interestingly, UDP-induced Orai1 mobilization to the peripheral region was greatly attenuated in STIM1−/− microglia. Their chemotactic migration defect was reproduced in vivo in embryonic brain; the aggregated number of STIM1−/− 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 STIM1−/− microglia. These in vitro and in vivo results suggest that STIM1-mediated store-operated calcium entry is important for the regulation of global [Ca2+]i changes which differentiates into active immune state of microglia, but it is more crucial for the regulation of local [Ca2+] microdomains which mediates the acute motility of murine microglia.
Highlights
Microglia are resident macrophages in the brain that orchestrate inflammatory responses
We investigate the function of STIM1-mediated store-operated calcium entry (SOCE) in pathogen- or purinergic-mediated microglial immune function using STIM1−/− mice, which have complete depletion of STIM1
After 40 min of uridine 5-(trihydrogen diphosphate) sodium salt (UDP) treatment, Orai1 clusters in the peripheral region were significantly increased, and some of them were colocalized with STIM1 clusters in WT microglia (Figure 4(a)). Such clusters of Orai1 in peripheral regions were not observed in STIM1−/− microglia (Figure 4(b)). These results suggested that STIM1 regulates Orai1 localization upon UDP treated conditions, and it might imply that STIM1 controls [Ca2+] microdomains in the cell periphery that requires for local Ca2+ signalling for phagocytic or chemotactic migration movements
Summary
Microglia are resident macrophages in the brain that orchestrate inflammatory responses. Foreign material, and pathological alterations in the brain [1, 2]. Pathological stimuli such as lipopolysaccharide (LPS) activate microglia and induce several morphological changes, including phagocytosis to remove cellular debris, and secretion of chemical mediators such as proinflammatory cytokines, which propagate immunological activities [1]. LPS induces a shift in the microglial gene expression profile, which is mainly mediated by the NFAT (Nuclear factor of activated T-cell) transcription factor [6]. Activated microglia have different gene expression profiles, secrete cytokines such as TNF-alpha and IL-6 and have the enhanced opsonin-dependent phagocytotic activity [6]. Chronic elevation of [Ca2+]i boosts phagocytosis and migration via optimizing the related gene expressions, but Mediators of Inflammation
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