STIM1 calcium sensor is required for activation of the phagocyte oxidase during in flammation and host defense

Hong Zhang, Regina A. Clemens, Fengchun Liu, Yongmei Hu, Yoshihiro Baba, Pierre Theodore, Tomohiro Kurosaki, Clifford A. Lowell

Research output: Contribution to journalArticle

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Abstract

The stromal-interactingmolecule 1 (STIM1) is a potent sensor of intracellular calcium, which in turn regulates entry of external calcium through plasmamembrane 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 Fcγ-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 α and β (PKCα and PKCβ), 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.

Original languageEnglish
Pages (from-to)2238-2249
Number of pages12
JournalBlood
Volume123
Issue number14
DOIs
Publication statusPublished - Apr 3 2014

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Phagocytes
Oxidoreductases
Chemical activation
Calcium
Sensors
Calcium Signaling
Superoxides
Neutrophils
Neutrophil Activation
Fc Receptors
Reperfusion Injury
Phagocytosis
GTP-Binding Proteins
Bacterial Infections
Integrins
Protein-Tyrosine Kinases
Protein Kinase C
Ligation
Lymphocytes
Protein Isoforms

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

STIM1 calcium sensor is required for activation of the phagocyte oxidase during in flammation and host defense. / Zhang, Hong; Clemens, Regina A.; Liu, Fengchun; Hu, Yongmei; Baba, Yoshihiro; Theodore, Pierre; Kurosaki, Tomohiro; Lowell, Clifford A.

In: Blood, Vol. 123, No. 14, 03.04.2014, p. 2238-2249.

Research output: Contribution to journalArticle

Zhang, H, Clemens, RA, Liu, F, Hu, Y, Baba, Y, Theodore, P, Kurosaki, T & Lowell, CA 2014, 'STIM1 calcium sensor is required for activation of the phagocyte oxidase during in flammation and host defense', Blood, vol. 123, no. 14, pp. 2238-2249. https://doi.org/10.1182/blood-2012-08-450403
Zhang, Hong ; Clemens, Regina A. ; Liu, Fengchun ; Hu, Yongmei ; Baba, Yoshihiro ; Theodore, Pierre ; Kurosaki, Tomohiro ; Lowell, Clifford A. / STIM1 calcium sensor is required for activation of the phagocyte oxidase during in flammation and host defense. In: Blood. 2014 ; Vol. 123, No. 14. pp. 2238-2249.
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