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

Abstract

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.

Microglial ablation in rats disrupts the circadian system

“…Importantly, within this time frame, we have seen no evidence of elevated pro-inflammatory cytokines, anxiety, withdrawal from exploratory activity in a new environment, memory deficits or visceral nausea to suggest a sickness response is accounting for these profiles. 8,9,21 The resulting diurnal profiles are consistent with a shift to inactive phase (light)-like behaviors throughout the day and night. Notably, these diurnal shifts in the physiological rhythms measured here were also accompanied by shifts in central clock genes and proteins.…”

“…They do not have memory deficits or visceral nausea. They also do not have elevated circulating cytokines, significant changes in brain cytokine concentrations or changes in brain or liver cytokine gene expression, 8,9,21 together illustrating that any changes in diurnal rhythms as a result of the microglial depletion would be independent of sickness or an immune response. Here, we investigate diurnal rhythms subject to standard 12 hour light cues, true circadian rhythms being endogenous rhythms occurring even in the absence of such cues.…”

Choroid plexus enlargement is associated with neuroinflammation and reduction of blood brain barrier permeability in depression

“…This may be protective in the short term but, if the inflammatory status becomes chronic, may disturb brain homeostasis and induce microglia to react to the disturbed environment. Very recent work on immune peripheral activation via LPS in mice and rats supports this view by showing that sickness behaviour is not mediated by microglia, hence their activation is a secondary result of the peripheral immune challenge (Vichaya et al, 2020).…”

Underestimated Peripheral Effects Following Pharmacological and Conditional Genetic Microglial Depletion

“…These results implicate that CSF1R inhibitors specifically target microglia in the CNS, and reference to influences on peripheral immunity (without detailed testing) have been made [ 23 ]. However, emerging data has inferred the opposite conclusion that the gene expression csf1r of liver tissue macrophages can be reduced using both Cx3cr1 -DTR rats and PLX5622 treatment [ 24 ]. PLX5622 diet at a concentration of 1200 mg/kg for 21 days, frequently used in research settings, could reduce the numbers of macrophages and monocytes in the periphery [ 25 ].…”