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TGFβ produced by IL‐10 redirected astrocytes attenuates microglial activation
Open accessAbstract
While there clearly is an intimate relationship between astrocytes and microglia, few studies have examined these potentially dynamic interactions. In this study, cytokine‐mediated communication between microglia and astrocytes under inflammatory conditions was investigated. We have previously shown that activated microglia produce Interleukin (IL)‐10, a regulatory cytokine that plays an important role in resolving neuroinflammation. Nonetheless, the mechanism by which IL‐10 attenuates pro‐inflammatory cytokine expression in the brain is unclear. Here, we show that IL‐10 redirected astrocytes regulate the activation of microglia in a transforming growth factor (TGF)‐β dependent manner. In support of this concept, astrocytes in the brain maintained higher IL‐10 receptor (IL‐10R1) expression and primary astrocytes in culture were markedly more sensitive to the anti‐inflammatory effects of IL‐10 compared with microglia. Moreover, studies using primary cultures and an astrocyte‐microglia coculture system revealed that astrocytes mediated the anti‐inflammatory effects of IL‐10 on microglia through the production of TGFβ. For instance, only when astrocytes were present did IL‐10 stimulation reduce the expression of IL‐1β and increase expression of anti‐inflammatory mediators fractalkine receptor (CX 3 CR1) and interleukin 4 receptor‐α (IL‐4Rα) in microglia. Importantly, these IL‐10‐astrocyte dependent effects on microglia were blocked by a TGFβ inhibitor. Furthermore, inhibition of TGFβ signaling in the brain resulted in prolonged sickness behavior and amplified pro‐inflammatory cytokine expression in mice challenged with lipopolysaccharide. Taken together, IL‐10 stimulated the production of TGFβ by astrocytes, which in turn, attenuated microglial activation. Overall, these findings provide novel insight into the mechanisms by which astrocytes modulate microglia under inflammatory conditions. GLIA 2014;62:881–895
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“A recent study showed that microglial IL-10 binds to astrocytes that modulate microglial inflammatory signaling in a transforming growth factor (TGF)-β-dependent manner (Norden et al, 2014).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Norden et al, 2014
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Metadata
- Authors
- Norden, D. M., Fenn, A. M., Dugan, A., & Godbout, J. P.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Godbout, Jonathan P.
- ORCID
- Godbout, Jonathan P.
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2014-02-25
- Volume
- 62
- Issue
- 6
- Pages
- 881-895
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC4061706
- OpenAlex
- W1568207206
- Cited by
- 332
- References
- 54
- Citations by year
- 2026: 28 · 2025: 38 · 2024: 33 · 2023: 48 · 2022: 23 · 2021: 29 · 2020: 29 · 2019: 23 · 2018: 28 · 2017: 11 · 2016: 17 · 2015: 16 · 2014: 9
- FWCI
- 9.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (R01AG033028)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- IL-10, TGF-beta, astrocytes, microglial activation, astrocyte-microglia interaction, neuroinflammation, IL-10 receptor, IL-1β, CX3CR1, IL-4 receptor alpha, sickness behavior, lipopolysaccharide, anti-inflammatory signaling
- MeSH terms
- Animals, Animals, Newborn, Astrocytes, Cells, Cultured, Mice, Inbred BALB C, Transforming Growth Factor beta, Interleukin-10, Microglia, Coculture Techniques, Mice
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