IL-10 Controls Early Microglial Phenotypes and Disease Onset in ALS Caused by Misfolded Superoxide Dismutase 1
Open accessAbstract
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.
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In vitro, upregulated IL-10 delayed the occurrence of disease.
“In vitro studies found that upregulated IL-10 delayed the occurrence of the disease.355”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [355]
The anti-inflammatory cytokine IL-10 was upregulated in microglia at pre-symptomatic stages in SOD1 mice.
“The anti-inflammatory cytokine IL-10 was upregulated in microglia at pre-symptomatic stages in SOD1 mice.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [355]
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- Authors
- Gravel, M., Béland, L.-C., Soucy, G., Abdelhamid, E., Rahimian, R., Gravel, C., & Kriz, J.
- Affiliations
- Université Laval (CA)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-01-20
- Volume
- 36
- Issue
- 3
- Pages
- 1031-1048
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6601999
- OpenAlex
- W2312354603
- Cited by
- 117
- References
- 56
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 18 · 2023: 16 · 2022: 2 · 2021: 11 · 2020: 17 · 2019: 12 · 2018: 8 · 2017: 12 · 2016: 3
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- ALS Society of Canada
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- amyotrophic lateral sclerosis, microglia, IL-10, SOD1 mutations, SOD1 G93A mice, disease onset, microglial activation, anti-inflammatory cytokines, innate immunity, TLR2, lipopolysaccharide challenge, gene therapy, neuroinflammation
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Brain, Cells, Cultured, Female, Male, Mice, Transgenic, Phenotype, Superoxide Dismutase, Interleukin-10, Protein Folding, Microglia, Mice
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