UDP-Induced Phagocytosis and ATP-Stimulated Chemotactic Migration Are Impaired in Microglia In Vitro and In Vivo.

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.