CCL5 evokes calcium signals in microglia through a kinase-, phosphoinositide-, and nucleotide-dependent mechanism

C. R. Shideman, S. Hu, P. K. Peterson, S. A. Thayer

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Microglia, the resident macrophages of the CNS, are responsible for the innate immune response in the brain and participate in the pathogenesis of certain neurodegenerative disorders. Chemokines initiate activation and migration of microglia. The β-chemokine CCL5 induces an elevation in intracellular calcium concentration ([Ca2+]i) in human microglia. Here, we examined the signal transduction pathway linking activation of chemokine receptor CCR5 to an elevation in [Ca2+]i in cultured microglia by using pharmacological approaches in combination with Fura-2-based digital imaging. The CCL5-induced response required Janus kinase (Jak) activity and the stimulation of an inhibitory G protein. Multiple downstream signaling pathways were involved, including phosphatidylinositol 3-kinase (PI3K), Bruton's tyrosine kinase (Btk), and phospholipase C (PLC)-mediated release of Ca2+ from inositol 1,4,5-trisphosphate (IP3)-sensitive stores. Activation of both the kinase and the lipase pathways was required for eliciting the Ca2+ response. However, the majority of the [Ca2+]i increase was derived from sources activated by NAD metabolites. Cyclic ADP-ribose (cADPR) evoked Ca2+ release from intracellular stores, and ADPR evoked Ca2+ influx via a nimodipine-sensitive channel. Thus, a multistep cascade couples CCR5 activation to Ca2+ increases in human microglia. Because changes in [Ca 2+]i affect chemotaxis, secretion, and gene expression, pharmacologic modulation of this pathway may alter inflammatory and degenerative processes in the CNS.

Original languageEnglish (US)
Pages (from-to)1471-1484
Number of pages14
JournalJournal of Neuroscience Research
Volume83
Issue number8
DOIs
StatePublished - Jun 2006

Keywords

  • Chemokine
  • Cyclic ADP-ribose
  • Microglia
  • Phosphatidylinositol 3-kinase
  • Phospholipase C

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