Hoffmann, Anja;
Kann, Oliver;
Ohlemeyer, Carsten;
Hanisch, Uwe-Karsten;
Kettenmann, Helmut
Elevation of Basal Intracellular Calcium as a Central Element in the Activation of Brain Macrophages (Microglia): Suppression of Receptor-Evoked Calcium Signaling and Control of Release Function
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Media type:
E-Article
Title:
Elevation of Basal Intracellular Calcium as a Central Element in the Activation of Brain Macrophages (Microglia): Suppression of Receptor-Evoked Calcium Signaling and Control of Release Function
Description:
<jats:p>Microglia–brain macrophages are immune-competent cells of the CNS and respond to pathologic events. Using bacterial lipopolysaccharide (LPS) as a tool to activate cultured mouse microglia, we studied alterations in the intracellular calcium concentration ([Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>) and in the receptor-evoked generation of transient calcium signals. LPS treatment led to a chronic elevation of basal [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>along with a suppression of evoked calcium signaling, as indicated by reduced [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>transients during stimulation with UTP and complement factor 5a. Presence of the calcium chelator BAPTA prevented the activation-associated changes in [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>and restored much of the signaling efficacy. We also evaluated downstream consequences of a basal [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>lifting during microglial activation and found BAPTA to strongly attenuate the LPS-induced release of nitric oxide (NO) and certain cytokines and chemokines. Furthermore, microglial treatment with ionomycin, an ionophore elevating basal [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>, mimicked the activation-induced calcium signal suppression but failed to induce release activity on its own. Our findings suggest that chronic elevation of basal [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>attenuates receptor-triggered calcium signaling. Moreover, increased [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>is required, but by itself is not sufficient, for release of NO and certain cytokines and chemokines. Elevation of basal [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub>could thus prove a central element in the regulation of executive functions in activated microglia.</jats:p>