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. 2014 Feb:40:191-200.
doi: 10.1016/j.psyneuen.2013.11.006. Epub 2013 Nov 27.

Chronic exposure to exogenous glucocorticoids primes microglia to pro-inflammatory stimuli and induces NLRP3 mRNA in the hippocampus

Matthew G Frank  1 , Sarah A Hershman  2 , Michael D Weber  2 , Linda R Watkins  2 , Steven F Maier  2
Affiliations

Chronic exposure to exogenous glucocorticoids primes microglia to pro-inflammatory stimuli and induces NLRP3 mRNA in the hippocampus

Matthew G Frank et al. Psychoneuroendocrinology. 2014 Feb.

Abstract

Chronic stress as well as chronic treatment with glucocorticoids (GCs) primes the neuroinflammatory response to a subsequent pro-inflammatory challenge. However, it remains unclear whether chronic GCs sensitize the response of key CNS immune substrates (i.e. microglia) to pro-inflammatory stimuli. In the present set of studies, male Sprague-Dawley rats underwent sham surgery or were adrenalectomized and then treated with varying concentrations of corticosterone (CORT; 0, 25, 50, and 75 μg/ml) administered in their drinking water. After 10 days of CORT exposure, whole hippocampus was collected and expression of glial activation markers measured or hippocampal microglia were isolated and challenged with LPS to probe for CORT-induced sensitization of pro-inflammatory responses. Chronic CORT exposure increased the gene expression of NLRP3, Iba-1, MHCII, and NF-κBIα in a concentration dependent manner. Chronic CORT (75 μg/ml) exposure potentiated the microglial proinflammatory response (TNFα, IL-1β, IL-6 and NLRP3) to LPS compared to the microglial response of sham surgery animals treated with vehicle. The present set of results demonstrate that chronic exposure to GCs primes microglia to pro-inflammatory stimuli and add to a growing body of evidence suggesting that a permissive function of GCs is that of an endogenous danger signal or alarmin.

Keywords: Glucocorticoids; Inflammasome; Microglia; Neuroinflammation; Priming; Stress.

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Conflict of interest statement

Conflict of interest

The authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Effect of chronic CORT exposure on serum and hippocampal CORT levels. Animals were ADX or subject to sham surgery. Sham surgery animals (0 μg/ml) were administered vehicle (0.4% ETOH) and ADX animals were administered CORT (25, 50, and 75 μg/ml) supplemented with 0.9% saline in their drinking water for 10 d. On day 10 of treatment, serum (Panel A) and hippocampal (Panel B) CORT levels were measured. Data are presented as the mean + sem. Significant group differences between different CORT treatment groups are designated as * p < 0.05, ** p < 0.01 and *** p < 0.001.
Fig. 2
Fig. 2
Effect of chronic CORT exposure on body weight. Animals were ADX or subject to sham surgery. Sham surgery animals (0 μg/ml CORT) were administered vehicle (0.4% ETOH) and ADX animals were administered CORT supplemented with 0.9% saline in their drinking water for 10 d. Percent change in body weight was measured 2, 4, 7 and 10 d post-surgery in animals treated with 0 μg/ml, 25 μg/ml, 50 μg/ml, and 75 μg/ml CORT. Data are presented as the mean + sem. Significant group differences between different CORT treatment groups are designated as * p < 0.05, ** p < 0.01 and **** p < 0.0001.
Fig. 3
Fig. 3
Effect of chronic CORT exposure on hippocampal macrophage/microglia activation markers and NLRP3 inflammasome components. Animals were ADX or subject to sham surgery. Sham surgery animals (0 μg/ml CORT) were administered vehicle (0.4% ETOH) and ADX animals were administered CORT supplemented with 0.9% saline in their drinking water for 10 d. Animals were treated with 0 μg/ml, 25 μg/ml, 50 μg/ml, and 75 μg/ml CORT. Ten days post-treatment, relative gene expression was measured in hippocampus. Data are presented as the mean + sem. For each gene, significant group differences between different CORT treatment groups are designated as * p < 0.05, ** p < 0.01 and *** p < 0.001.
Fig. 4
Fig. 4
Effect of chronic CORT exposure on hippocampal IL-1β protein. Animals were ADX or subject to sham surgery. Sham surgery animals (0 μg/ml CORT) were administered vehicle (0.4% ETOH) and ADX animals were administered CORT supplemented with 0.9% saline in their drinking water for 10 d. Animals were treated with 0 μg/ml, 25 μg/ml, 50 μg/ml, and 75 μg/ml CORT. Ten days post-treatment, IL-1β protein levels were measured in hippocampus. Data are presented as the mean + sem. Significant group differences between different CORT treatment groups are designated as ** p < 0.01.
Fig. 5
Fig. 5
Effect of chronic CORT exposure on water consumption behavior. Animals were ADX or subject to sham surgery. Sham surgery animals (0 μg/ml CORT) were administered vehicle (0.4% ETOH) and ADX animals were administered CORT (75 μg/ml) supplemented with 0.9% saline in their drinking water for 10 d. Water consumption was measured at 2, 4, 6, 8 and 10 d post-surgery. Data are presented as the mean + sem. At each time-point post-surgery, significant group differences between vehicle and CORT treatment are designated as * p < 0.05 and ** p < 0.01.
Fig. 6
Fig. 6
Effect of chronic CORT exposure on priming of hippocampal microglia. Animals were ADX or subject to sham surgery. Sham surgery animals (0 μg/ml CORT) were administered vehicle (0.4% ETOH) and ADX animals were administered CORT (75 μg/ml) supplemented with 0.9% saline in their drinking water for 10 d. Ten days post-treatment, hippocampal microglia were isolated and exposed to LPS for 2h and relative gene expression measured. Data are presented as the mean + sem. In the left hand column, vehicle (0 μg/ml) and CORT (75 μg/ml) treatment effects on pro-inflammatory cytokine levels were compared for each concentration of LPS. Significant mean differences are designated * p < 0.05, ** p < 0.01. In the right hand column, the area under the LPS concentration curve is presented for each gene and means compared for vehicle and CORT treated animals. Significant mean differences are designated * p < 0.05.
Fig. 6
Fig. 6
Effect of chronic CORT exposure on priming of hippocampal microglia. Animals were ADX or subject to sham surgery. Sham surgery animals (0 μg/ml CORT) were administered vehicle (0.4% ETOH) and ADX animals were administered CORT (75 μg/ml) supplemented with 0.9% saline in their drinking water for 10 d. Ten days post-treatment, hippocampal microglia were isolated and exposed to LPS for 2h and relative gene expression measured. Data are presented as the mean + sem. In the left hand column, vehicle (0 μg/ml) and CORT (75 μg/ml) treatment effects on pro-inflammatory cytokine levels were compared for each concentration of LPS. Significant mean differences are designated * p < 0.05, ** p < 0.01. In the right hand column, the area under the LPS concentration curve is presented for each gene and means compared for vehicle and CORT treated animals. Significant mean differences are designated * p < 0.05.
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