Journal
JOURNAL OF NEUROSCIENCE
Volume 36, Issue 3, Pages 1031-1048Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0854-15.2016
Keywords
ALS; biophotonics; innate immunity; microglia; TLR2; transgenic mice
Categories
Funding
- Muscular Dystrophy Association
- Canadian Institutes of Health Research
- Amyotrophic Lateral Sclerosis Society of Canada
- Fonds de recherche du Quebec en Sante
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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 SOD1G93A and SOD1G37R 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 SOD1G93A 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.
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