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Regional differences in the inflammatory and heat shock response in glia: implications for ALS

Clarke, BE; Gil, RS; Yip, J; Kalmar, B; Greensmith, L; (2019) Regional differences in the inflammatory and heat shock response in glia: implications for ALS. Cell Stress Chaperones 10.1007/s12192-019-01005-y. (In press). Green open access

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Abstract

Preferential neuronal vulnerability is characteristic of several neurodegenerative diseases including the motor neuron disease amyotrophic lateral sclerosis (ALS). It is well established that glia play a critical role in ALS, but it is unknown whether regional differences in the ability of glia to support motor neurons contribute to the specific pattern of neuronal degeneration. In this study, using primary mixed glial cultures from different mouse CNS regions (spinal cord and cortex), we examined whether regional differences exist in key glial pathways that contribute to, or protect against, motor neuron degeneration. Specifically, we examined the NF-κB-mediated inflammatory pathway and the cytoprotective heat shock response (HSR). Glial cultures were treated with pro-inflammatory stimuli, tumour necrosis factor-ɑ/lipopolysaccharide or heat stressed to stimulate the inflammatory and HSR respectively. We found that spinal cord glia expressed more iNOS and produced more NO compared to cortical glia in response to inflammatory stimuli. Intriguingly, we found that expression of ALS-causing SOD1G93A did not elevate the levels of NO in spinal cord glia. However, activation of the stress-responsive HSR was attenuated in SOD1G93A cultures, with a reduced Hsp70 induction in response to stressful stimuli. Exposure of spinal cord glia to heat shock in combination with inflammatory stimuli reduced the activation of the inflammatory response. The results of this study suggest that impaired heat shock response in SOD1G93A glia may contribute to the exacerbated inflammatory reactions observed in ALS mice. Graphical abstract Mixed primary glial cultures were established from cortical and spinal cord regions of wild-type mice and mice expressing ALS-causing mutant human SOD1 and the inflammatory and heat shock responses were investigated in these cultures. In the absence of stress, all cultures appeared to have similar cellular composition, levels of inflammatory mediators and similar expression level of heat shock proteins. When stimulated, spinal cord glia were more reactive and activated the inflammatory pathway more readily than cortical glia; this response was similar in wild-type and SOD1G93A glial cultures. Although the heat shock response was similar in spinal cord and cortical glial, in SOD1G93A expressing glia from both the spinal cord and cortex, the induction of heat shock response was diminished. This impaired heat shock response in SOD1G93A glia may therefore contribute to the exacerbated inflammatory reactions observed in ALS mice.

Type: Article
Title: Regional differences in the inflammatory and heat shock response in glia: implications for ALS
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s12192-019-01005-y
Publisher version: https://doi.org/10.1007/s12192-019-01005-y
Language: English
Additional information: © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Keywords: ALS, Astroglia, Heat shock protein 70, Heat shock response, Inflammation, Microglia, NF-κB, NO, iNOS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > ION Central Administration
URI: https://discovery.ucl.ac.uk/id/eprint/10076194
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