Altered hypothalamic inflammatory gene expression correlates with heat stroke severity in a conscious rodent model

Abstract

It has been suggested that heat-induced hypothalamic damage mediates core temperature (Tc) disturbances during heat stroke (HS) recovery; this is significant as hypothermia and/or fever have been linked to severity and overall pathological insult. However, to date there has been a lack of histological evidence in support of these claims. We hypothesized that local hypothalamic cytokines and/or chemokines, known regulators of Tc, are mediating the elevation in Tc during HS recovery even in the absence of histological damage. In experiment 1, the hypothalamus of Fischer 344 rats was examined for 84 cytokine/chemokine genes (real-time PCR) at multiple time points (Tc,Max, 1, 3, and 10 days) during mild HS recovery. In experiment 2, the hypothalamus of three different HS severities (MILD, moderate [MOD], and severe [SEV]) in rats were examined for the same genes as experiment 1 as well as six oxidative damage markers, at a single intermediate time point (1 day). Systemic cytokines were also analyzed in experiment 2 across the three severities. There were significant alterations in 25 cytokines/chemokines expression at Tc,Max, but little or no changes in expression at longer time points in experiment 1. In experiment 2 there were significant changes in gene expression in SEV rats only, with MILD and MOD rats showing baseline expression at 1 day, despite an absence of systemic cytokine expression in any severity. There was also no change in any oxidative marker of damage at 1 day, regardless of severity. In conclusion, we show only limited changes during long term recovery from HS, but demonstrate differences in hypothalamic gene expression patterns that may be driving HS pathology and morbidity. These findings contribute to our overall understanding of HS pathology in the CNS, as well as providing avenues for future pharmacological intervention.

Embryonic Heat Conditioning Induces TET-Dependent Cross-Tolerance to Hypothalamic Inflammation Later in Life

“…Across different species, heat acclimation has been shown to protect against a wide range of stressors ( Shein et al, 2008 ; Umschwief et al, 2010 , Umschweif et al, 2014 ; Assayag et al, 2012 ; Horowitz, 2017 ; Pollak et al, 2017 ; Hossain et al, 2018 ). Various findings point to the hypothalamus as the site of convergence of thermal–inflammation-related networks ( Tzschentke, 2007 ; Tona et al, 2008 ; Tzschentke and Halle, 2009 ; Hueston and Deak, 2014 ; Loyau et al, 2014 , 2016 ; Chao et al, 2015 ; Klett et al, 2015 ; Nassar et al, 2015 ; Audet et al, 2016 ; Morrison, 2016 ).…”

Coagulopathy signature precedes and predicts severity of end-organ heat stroke pathology in a mouse model

“…We have presented in this work, to our knowledge, the first RNAseq analysis of tissue from an animal model of heat stroke. While other studies have presented gene expression assayed by quantitative PCR [27][28][29] , the advantage of RNAseq is the agnostic measure of the full transcriptome, rather than a set of pre-chosen RNAs. This agnostic search allows us to assay a greater extent of perturbation to the system state of the tissue, without narrowing our view with expectations.…”

Transcriptome Sequencing Reveals Astrocytes as a Therapeutic Target in Heat-Stroke

“…In terms of pathology, chemokines and chemokine receptors are involved in many CNS disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis [28]. A previous study revealed significant changes in the expression of 25 cytokines and chemokines in the hypothalamus of heat-stroke rats [3]. Our results showed that these changes may occur in astrocytes, rather than neurons, so the former may thereby contribute to neuroinflammation and aggravate neural injury.…”

“…It was surprising that C6, Ccl3, and Ccr1 were all up-regulated in RNA-seq and qPCR in primary astrocyte culture after heat stress, but down-regulated in heat-stroke rats. According to previous work on whole hypothalamic tissue, the transcriptional levels of CCL3 and CCR1 are down-regulated in heat-stroke rats [3]. In addition, down-regulation of C5, CCL12, CCL4, and CCR3 was found, while CCL6, CCR8, and CXCL13 were up-regulated.…”

“…During the 2003 heat-wave event in Europe, the high temperature caused an estimated 30,000 deaths [2]. Heat-stroke can induce severe CNS injury which is characterized by cognitive and motor deficits, and permanent brain damage and coma [3]. The CNS, which is particularly vulnerable to direct thermal effects, can also be injured by disruption of the blood-brain barrier (BBB) and brain edema [4].…”