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TLR Signaling Tailors Innate Immune Responses in Human Microglia and Astrocytes
Open accessAbstract
The specific signals mediating the activation of microglia and astrocytes as a prelude to, or consequence of, CNS inflammation continue to be defined. We investigated TLRs as novel receptors mediating innate immune responses in human glial cells. We find that microglia express mRNA for TLRs 1-9, whereas astrocytes express robust TLR3, low-level TLR 1, 4, 5, and 9, and rare-to-undetectable TLR 2, 6, 7, 8, and 10 mRNA (quantitative real-time PCR). We focused on TLRs 3 and 4, which can signal through both the MyD88-dependent and -independent pathways, and on the MyD88-restricted TLR2. By flow cytometry, we established that microglia strongly express cell surface TLR2; TLR3 is expressed at higher levels intracellularly. Astrocytes express both cell surface and intracellular TLR3. All three TLRs trigger microglial activation upon ligation. TLR3 signaling induces the strongest proinflammatory polarizing response, characterized by secretion of high levels of IL-12, TNF-alpha, IL-6, CXCL-10, and IL-10, and the expression of IFN-beta. CXCL-10 and IL-10 secretion following TLR4 ligation are comparable to that of TLR3; however, other responses were lower or absent. TLR2-mediated responses are dominated by IL-6 and IL-10 secretion. Astrocytes respond to TLR3 ligation, producing IL-6, CXCL-10, and IFN-beta, implicating these cells as contributors to proinflammatory responses. Initial TLR-mediated glial activation also regulates consequent TLR expression; while TLR2 and TLR3 are subject to positive feedback, TLR4 is down-regulated in microglia. Astrocytes up-regulate all three TLRs following TLR3 ligation. Our data indicate that activation of innate immune responses in the CNS is not homogeneous but rather tailored according to cell type and environmental signal.
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“Concretely, TLR4 and TLR2 are associated with both neuro-inflammation and clearance of protein aggregates in neurodegenerative disorders (Jack et al., 2005).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Jack et al., 2005
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Metadata
- Authors
- Jack, C. S., Arbour, N., Manusow, J., Montgrain, V., Blain, M., McCrea, E., Shapiro, A., & Antel, J. P.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-10-01
- Volume
- 175
- Issue
- 7
- Pages
- 4320-4330
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2165413779
- Cited by
- 734
- References
- 46
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 15 · 2023: 34 · 2022: 44 · 2021: 42 · 2020: 25 · 2019: 26 · 2018: 36 · 2017: 39 · 2016: 38 · 2015: 40 · 2014: 33 · 2013: 59 · 2012: 44
- FWCI
- 20.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- Toll-like receptors, microglia, astrocytes, glial activation, TLR3, TLR4, TLR2, MyD88 signaling, neuroinflammation, inflammatory cytokines, CXCL10, IL-10, interferon-beta, innate immunity
- MeSH terms
- Adult, Antigens, Differentiation, Astrocytes, Fetus, Humans, Immunity, Innate, Receptors, Immunologic, Signal Transduction, Interleukin-10, Microglia, Interleukin-12, Adaptor Proteins, Signal Transducing, Myeloid Differentiation Factor 88
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