SGK3 Regulates Ca(2+) Entry and Migration of Dendritic Cells

Overview

Journal Cell Physiol Biochem

Specialties Biochemistry
Cell Biology
Pharmacology

Date 2012 Nov 23

PMID 23171960

Citations 19

Authors

Evi Schmid

Madhuri Bhandaru

Meerim K Nurbaeva

Wenting Yang

Kalina Szteyn

Antonella Russo

Christina Leibrock

Leonid Tyan

David Pearce

Ekaterina Shumilina

Florian Lang

Affiliations

Soon will be listed here.

Abstract

Background/aims: Dendritic cells (DCs) are antigen-presenting cells linking innate and adaptive immunity. DC maturation and migration are governed by alterations of cytosolic Ca(2+) concentrations ([Ca(2+)](i)). Ca(2+) entry is in part accomplished by store-operated Ca(2+) (SOC) channels consisting of the membrane pore-forming subunit Orai and the ER Ca(2+) sensing subunit STIM. Moreover, DC functions are under powerful regulation of the phosphatidylinositol-3-kinase (PI3K) pathway, which suppresses proinflammatory cytokine production but supports DC migration. Downstream targets of PI3K include serum- and glucocorticoid-inducible kinase isoform SGK3. The present study explored, whether SGK3 participates in the regulation of [Ca(2+)](i) and Ca(2+)-dependent functions of DCs, such as maturation and migration.

Methods/results: Experiments were performed with bone marrow derived DCs from gene targeted mice lacking SGK3 (sgk3(-/-)) and DCs from their wild type littermates (sgk3(+/+)). Maturation, phagocytosis and cytokine production were similar in sgk3(-/-) and sgk3(+/+) DCs. However, SOC entry triggered by intracellular Ca(2+) store depletion with the endosomal Ca(2+) ATPase inhibitor thapsigargin (1 µM) was significantly reduced in sgk3(-/-) compared to sgk3(+/+) DCs. Similarly, bacterial lipopolysaccharide (LPS, 1 µg/ml)- and chemokine CXCL12 (300 ng/ml)- induced increase in [Ca(2+)](i) was impaired in sgk3(-/-) DCs. Moreover, currents through SOC channels were reduced in sgk3(-/-) DCs. STIM2 transcript levels and protein abundance were significantly lower in sgk3(-/-) DCs than in sgk3(+/+) DCs, whereas Orai1, Orai2, STIM1 and TRPC1 transcript levels and/or protein abundance were similar in sgk3-/- and sgk3(+/+) DCs. Migration of both, immature DCs towards CXCL12 and LPS-matured DCs towards CCL21 was reduced in sgk3(-/-) as compared to sgk3(+/+) DCs. Migration of sgk3(+/+) DCs was further sensitive to SOC channel inhibitor 2-APB (50 µM) and to STIM1/STIM2 knock-down.

Conclusion: SGK3 contributes to the regulation of store-operated Ca(2+) entry into and migration of dendritic cells, effects at least partially mediated through SGK3-dependent upregulation of STIM2 expression.

Citing Articles

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