TY - JOUR
T1 - UDP-induced phagocytosis and ATP-stimulated chemotactic migration are impaired in STIM1 -/- microglia in vitro and in vivo
AU - Lim, Hye Min
AU - Woon, Heo
AU - Han, Jung Woo
AU - Baba, Yoshihiro
AU - Kurosaki, Tomohiro
AU - Lee, Min Goo
AU - Kim, Joo Young
N1 - Funding Information:
This work was supported by grants from the National Research Foundation of Korea (NRF-2009-0090035, NRF- 2015R1D1A1A02062027, and MSIP-2013R1A3A2042197) and a faculty research grant fromthe Yonsei University College of Medicine for 2015 (6-2015-0048).
Publisher Copyright:
© 2017 Hye Min Lim et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.1155/2017/8158514
DO - 10.1155/2017/8158514
M3 - Article
C2 - 28293066
AN - SCOPUS:85014386669
SN - 0962-9351
VL - 2017
JO - Mediators of Inflammation
JF - Mediators of Inflammation
M1 - 8158514
ER -