Cited by 363Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology

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Guillot-Sestier, Marie-Victoire, Doty, Kevin R., Gate, David, Rodriguez, Javier, Leung, Brian P., Rezai-Zadeh, Kavon, Town, Terrence·2015·Neuron

Abstract

The impact of inflammation suppressor pathways on Alzheimer's disease (AD) evolution remains poorly understood. Human genetic evidence suggests involvement of the cardinal anti-inflammatory cytokine, interleukin-10 (IL10). We crossed the APP/PS1 mouse model of cerebral amyloidosis with a mouse deficient in Il10 (APP/PS1(+)Il10(-/-)). Quantitative in silico 3D modeling revealed activated Aβ phagocytic microglia in APP/PS1(+)Il10(-/-) mice that restricted cerebral amyloidosis. Genome-wide RNA sequencing of APP/PS1(+)Il10(-/-) brains showed selective modulation of innate immune genes that drive neuroinflammation. Il10 deficiency preserved synaptic integrity and mitigated cognitive disturbance in APP/PS1 mice. In vitro knockdown of microglial Il10-Stat3 signaling endorsed Aβ phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aβ uptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated in AD patient brains. Our results suggest that "rebalancing" innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD.

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Authors
Guillot-Sestier, M.-V., Doty, K. R., Gate, D., Rodriguez, J., Leung, B. P., Rezai-Zadeh, K., & Town, T.
Affiliations
  • University of Southern California (US)
  • Pennington Biomedical Research Center (US)
Corresponding author
Town, Terrence
Venue
Neuron
Publisher
Elsevier BV
Published
2015-02
Volume
85
Issue
3
Pages
534-548
ISSN
0896-6273 (ISSN-L)
OpenAlex
W1999516517
Cited by
363
References
79
Citations by year
2026: 19 · 2025: 18 · 2024: 30 · 2023: 26 · 2022: 33 · 2021: 34 · 2020: 39 · 2019: 33 · 2018: 28 · 2017: 41 · 2016: 43 · 2015: 19
FWCI
23.34
Type
journal article
Language
en
Open access
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (1f31ns083339-01a1)
  • National Institute on Aging (R00AG029726)
  • National Institute of Neurological Disorders and Stroke (1F31NS083339-01A1, R01NS076794)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
IL-10, Alzheimer's disease, APP/PS1 mice, cerebral amyloidosis, microglia, amyloid-beta phagocytosis, innate immunity, neuroinflammation, STAT3 signaling, apolipoprotein E, synaptic integrity, cognitive impairment, anti-inflammatory cytokines
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Female, Humans, Immunity, Innate, Male, Mice, Inbred C57BL, Mice, Transgenic, Interleukin-10, Mice, Knockout, Mice

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