Journal
BLOOD
Volume 123, Issue 14, Pages 2238-2249Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-08-450403
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Funding
- National Institutes of Health, National Institute of Allergy and Infectious Diseases [AI65495, AI68150]
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [K12-HD000850]
- Grants-in-Aid for Scientific Research [21229007] Funding Source: KAKEN
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The stromal-interacting molecule 1 (STIM1) is a potent sensor of intracellular calcium, which in turn regulates entry of external calcium through plasma membrane channels to affect immune cell activation. Although the contribution of STIM1 to calcium signaling in lymphocytes has been well studied, the role of this protein in neutrophil-mediated inflammation and host defense is unknown. We report that STIM1-deficient murine neutrophils show loss of store-operated calcium entry (SOCE) in response to both soluble ligands that activate G-proteins as well as Fc gamma-receptor or integrin ligation that activates tyrosine kinase signaling. This results in modest defects in phagocytosis and degranulation responses but a profound block in superoxide production by the phagocyte oxidase. We trace the primary intracellular target of calcium to be protein kinase C isoforms alpha and beta (PKC alpha and PKC beta), which in turn phosphorylate subunits of the oxidase leading to superoxide production. In vivo the loss of SOCE in stim1(-/-) chimeric mice results in marked susceptibility to bacterial infections but also protection from tissue injury in hepatic ischemia/reperfusion injury. These results demonstrate the critical role of STIM1-mediated SOCE and define major protein targets of calcium signaling in neutrophil activation during inflammatory disease.
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