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.
Highlights
Microglia constitutes the macrophage equivalent of the CNS
We evaluated downstream consequences of a basal [Ca2ϩ]i lifting during microglial activation and found BAPTA to strongly attenuate the LPS-induced release of nitric oxide (NO) and certain cytokines and chemokines
We present evidence that the rise in [Ca 2ϩ]i is necessary to allow for characteristic features of microglial activation, such as release of nitric oxide (NO) and certain cytokines and chemokines
Summary
Microglia constitutes the macrophage equivalent of the CNS. In response to pathological events, the normally “resting” microglia gradually transform into motile, secretory active and potentially cytotoxic phagocytes (Kreutzberg, 1996; Schwaiger et al, 1998; Raivich et al, 1999a; Streit et al, 2000; Hanisch, 2001). Activated microglial cells participate in mechanisms of innate and immune defense, tissue repair, and neuroprotection. Experimental and clinical evidence supports the notion that excessive microglial activation exacerbates destructive cascades. Microglia express a variety of receptors that allow for a monitoring of the surrounding tissue (Norenberg et al, 1994; Kreutzberg, 1996; Streit et al, 2000). Receptors for neurotransmitters and cotransmitters could be important for sensing neuronal activity, and microglia express functional glutamatergic, adrenergic, and purinoreceptors (Noda et al, 2000; Prinz et al, 2001).
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