Journal Article

Microglia depletion fails to abrogate inflammation-induced sickness in mice and rats

Vichaya, Elisabeth G., Spencer, Sarah J., Dantzer, Robert, Ford, Bianca G., Malik, Sajida, Sominsky, Luba

2020

Overview

Background 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. Methods Depletion 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. Results Chronic 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. Conclusions These findings reveal that the sickness-inducing effects of acute inflammation can develop independently of microglia activation.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Behavior / Biomedical and Life Sciences / Biomedicine / Blood-brain barrier / Body weight / Body weight loss / Brain / Brain - immunology / Brain - metabolism / Colony-stimulating factor / CSF-1 receptor antagonism / Cx3cr1 / CX3CR1 protein / Cytokines / Development and progression / Diet / Diphtheria / Diphtheria toxin / Experiments / Fractalkine / Gene expression / Genetic engineering / Humidity / Hypothalamus / Illness Behavior - physiology / Immunology / Inflammation / Inflammation - chemically induced / Inflammation - immunology / Laboratory animals / Lipopolysaccharide / Lipopolysaccharides / Lipopolysaccharides - toxicity / Locomotor activity / Macrophages / Mice / Mice, Inbred C57BL / Microglia / Microglial cells / Neurobiology / Neurology / Neurosciences / Oral administration / Physiological aspects / PLX5622 / Rats / Rats, Wistar / Rodents / Wheel running