Abstract
BackgroundProduction of inflammatory mediators by reactive microglial cells in the brain is generally considered the primary mechanism underlying the development of symptoms of sickness in response to systemic inflammation.MethodsDepletion of microglia was achieved in C57BL/6 mice by chronic oral administration of PLX5622, a specific antagonist of colony stimulating factor-1 receptor, and in rats by a knock-in model in which the diphtheria toxin receptor was expressed under the control of the endogenous fractalkine receptor (CX3CR1) promoter sequence. After successful microglia depletion, mice and rats were injected with a sickness-inducing dose of lipopolysaccharide according to a 2 (depletion vs. control) × 2 (LPS vs. saline) factorial design. Sickness was measured by body weight loss and decreased locomotor activity in rats and mice, and reduced voluntary wheel running in mice.ResultsChronic administration of PLX5622 in mice and administration of diphtheria toxin to knock-in rats depleted microglia and peripheral tissue macrophages. However, it did not abrogate the inducible expression of proinflammatory cytokines in the brain in response to LPS and even exacerbated it for some of the cytokines. In accordance with these neuroimmune effects, LPS-induced sickness was not abrogated, rather it was exacerbated when measured by running wheel activity in mice.ConclusionsThese findings reveal that the sickness-inducing effects of acute inflammation can develop independently of microglia activation.
Highlights
Inflammation induces symptoms of sickness that are characterized by malaise, decreased appetite, fatigue, reduced sociability, increased slow wave sleep, and fever [1]
There are several ways of genetically depleting microglia from knocking out genes that are essential for the survival and development of microglia to administration of immunotoxins such as diphtheria toxin to target the diphtheria toxin receptor genetically inserted in myeloid cells that express the fractalkine receptor CX3C chemokine receptor 1 (CX3CR1) [12]
We used the brain penetrant colony stimulating factor-1 receptor (CSF-1R) antagonist PLX-5622 [13, 14] in mice and a knock-in rat model in which a diphtheria receptor is expressed under the control of the endogenous Cx3cr1 promoter sequence [15, 16]
Summary
Inflammation induces symptoms of sickness that are characterized by malaise, decreased appetite, fatigue, reduced sociability, increased slow wave sleep, and fever [1]. Based on the observation that the development and survival of microglia critically depends on colony stimulating factor-1 receptor (CSF-1R) signaling [11], CSF-1R antagonists have been successfully developed and are commonly used to eliminate microglia Continuous administration of these molecules to mice via their food results in a gradual depletion of Iba-1 and CD68 positive microglia in the brain within a few days of treatment, which persists until cessation of treatment and is followed by repopulation [10]. The objective of the present study was to determine whether ablation of microglia is sufficient to abrogate the behavioral signs of sickness induced by systemic administration of lipopolysaccharide (LPS) to mice and rats For this purpose, we used the brain penetrant CSF-1R antagonist PLX-5622 [13, 14] in mice and a knock-in rat model in which a diphtheria receptor is expressed under the control of the endogenous Cx3cr promoter sequence [15, 16]. Production of inflammatory mediators by reactive microglial cells in the brain is generally considered the primary mechanism underlying the development of symptoms of sickness in response to systemic inflammation
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