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.
abstract: 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 2+]i) and in the receptor-evoked generation of transient calcium signals. LPS treatment led to a chronic elevation of basal [Ca 2+]i along with a suppression of evoked calcium signaling, as indicated by reduced [Ca 2+]i transients during stimulation with UTP and complement factor 5a. Presence of the calcium chelator BAPTA prevented the activation-associated changes in [Ca 2+]i and restored much of the signaling efficacy. We also evaluated downstream consequences of a basal [Ca 2+]i 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 2+]i, 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 2+]i attenuates receptor-triggered calcium signaling. Moreover, increased [Ca 2+]i is required, but by itself is not sufficient, for release of NO and certain cytokines and chemokines. Elevation of basal [Ca 2+]i could thus prove a central element in the regulation of executive functions in activated microglia.
authors.affiliation: Department of Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, D-13092 Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Oliver
authors.initials: O
authors.lastname: Kann
authors.forename: Carsten
authors.initials: C
authors.lastname: Ohlemeyer
authors.forename: Uwe-Karsten
authors.initials: UK
authors.lastname: Hanisch
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D018925:Chemokines / Q000378:metabolism; D015936:Complement C5a / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D011951:Receptors, Complement / Q000378:metabolism; D011983:Receptors, Purinergic / Q000378:metabolism; D014544:Uridine Triphosphate / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D018925:Chemokines; D016207:Cytokines; D007476:Ionophores; D008070:Lipopolysaccharides; D011951:Receptors, Complement; D011983:Receptors, Purinergic; D009569:Nitric Oxide; D004533:Egtazic Acid; D015759:Ionomycin; D015936:Complement C5a; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium; D014544:Uridine Triphosphate