title: IL-10 Controls Early Microglial Phenotypes and Disease Onset in ALS Caused by Misfolded Superoxide Dismutase 1.
abstract: While reactive microgliosis is a hallmark of advanced stages of amyotrophic lateral sclerosis (ALS), the role of microglial cells in events initiating and/or precipitating disease onset is largely unknown. Here we provide novel in vivo evidence of a distinct adaptive shift in functional microglial phenotypes in preclinical stages of superoxide dismutase 1 (SOD1)-mutant-mediated disease. Using a mouse model for live imaging of microglial activation crossed with SOD1(G93A) and SOD1(G37R) mouse models, we discovered that the preonset phase of SOD1-mediated disease is characterized by development of distinct anti-inflammatory profile and attenuated innate immune/TLR2 responses to lipopolysaccharide (LPS) challenge. This microglial phenotype was associated with a 16-fold overexpression of anti-inflammatory cytokine IL-10 in baseline conditions followed by a 4.5-fold increase following LPS challenge. While infusion of IL-10R blocking antibody, initiated at day 60, caused a significant increase in markers of microglial activation and precipitated clinical onset of disease, a targeted overexpression of IL-10 in microglial cells, delivered via viral vectors expressed under CD11b promoter, significantly delayed disease onset and increased survival of SOD1(G93A) mice. We propose that the high IL-10 levels in resident microglia in early ALS represent a homeostatic and compensatory "adaptive immune escape" mechanism acting as a nonneuronal determinant of clinical onset of disease. Significance statement: We report here for the first time that changing the immune profile of brain microglia may significantly affect clinical onset and duration of disease in ALS models. We discovered that in presymptomatic disease microglial cells overexpress anti-inflammatory cytokine IL-10. Given that IL-10 is major homeostatic cytokine and its production becomes deregulated with aging, this may suggest that the capacity of microglia to adequately produce IL-10 may be compromised in ALS. We show that blocking IL-10 increased inflammation and precipitated clinical disease onset, whereas overexpression of IL-10 in microglia using a gene therapy approach significantly delayed disease onset and increased survival of ALS mice. Based on our results, we propose that targeted overexpression of IL-10 in microglia may have therapeutic potential in ALS.
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Research Centre of the Mental Health Institute of Quebec, Laval University, Quebec, Quebec G1J 2G3, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Gravel
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Research Centre of the Mental Health Institute of Quebec, Laval University, Quebec, Quebec G1J 2G3, Canada.
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Béland
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Research Centre of the Mental Health Institute of Quebec, Laval University, Quebec, Quebec G1J 2G3, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Soucy
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Research Centre of the Mental Health Institute of Quebec, Laval University, Quebec, Quebec G1J 2G3, Canada.
authors.forename: Essam
authors.identifier: http://orcid.org/0000-0002-2022-5229
authors.initials: E
authors.lastname: Abdelhamid
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Research Centre of the Mental Health Institute of Quebec, Laval University, Quebec, Quebec G1J 2G3, Canada.
authors.forename: Reza
authors.initials: R
authors.lastname: Rahimian
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Research Centre of the Mental Health Institute of Quebec, Laval University, Quebec, Quebec G1J 2G3, Canada.
authors.forename: Claude
authors.initials: C
authors.lastname: Gravel
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Research Centre of the Mental Health Institute of Quebec, Laval University, Quebec, Quebec G1J 2G3, Canada jasna.kriz@fmed.ulaval.ca.
authors.forename: Jasna
authors.initials: J
authors.lastname: Kriz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D010641:Phenotype; D017510:Protein Folding; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C556062:IL10 protein, mouse; D016753:Interleukin-10; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: ALS; TLR2; biophotonics; innate immunity; microglia; transgenic mice