Cited by 735Neuroinflammation and Neurodegeneration MechanismsImmune Response and InflammationInflammasome and immune disorders

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TLR Signaling Tailors Innate Immune Responses in Human Microglia and Astrocytes

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Jack, Carolyn S, Arbour, Nathalie, Manusow, Joshua, Montgrain, Vivianne, Blain, Manon, McCrea, Ellie, Shapiro, Aaron, Antel, Jack P·2005·The Journal of Immunology

DOI 10.4049/jimmunol.175.7.4320

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Abstract

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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“In this scheme, we propose that the reported low abundance of LPS receptor on astrocytes (Jack et al. 2005) indicates that LPS directly stimulates the expression of TIMP-2, MMP-12 and MMP-13 genes by microglia.”
Use of human MonoMac6 cells for development of in vitro assay predictive of adjuvant safety in vivo
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Different TLR4 expression and microglia/macrophage activation induced by hemorrhage in the rat spinal cord after compressive injury
Zhang, Y.-K., Liu, J., Peng, Z., Fan, H., Yao, A., Peng, C., Liu, L., Ju, G., & Kuang, F. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-112 · Cited by 60
“TLR signals tailor the innate immune response [18], which is vital for the CNS restoration of tissue repair and hemoestasis [19].”
Background
NADPH oxidase-mediated redox signal contributes to lipoteichoic acid-induced MMP-9 upregulation in brain astrocytes
Hsieh, H., Lin, C., Shih, R., Hsiao, L., & Yang, C. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-110 · Cited by 60
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Apigenin Attenuates Functional and Structural Alterations via Targeting NF-kB/Nrf2 Signaling Pathway in LPS-Induced Parkinsonism in Experimental Rats
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“In brain, TLRs are primarily expressed in immune cells such as microglia and astrocytes.”
BackgroundInfluential
Neuronal toll-like receptors and neuro-immunity in Parkinson's disease, Alzheimer's disease and stroke
Rietdijk, C. D., Wezel, R. J. A. V., Garssen, J., & Kraneveld, A. D. (2016) · Neuroimmunology and Neuroinflammation · doi:10.20517/2347-8659.2015.28 · Cited by 59
“[9-15] More specifically, in the CNS neurons, astrocytes and microglial cells express TLR1-9, whereas oligodendrocytes express only TLR2 and TLR3.”
Influential
Diosgenin Attenuates Lipopolysaccharide-Induced Parkinson’s Disease by Inhibiting the TLR/NF-κB Pathway
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Fullerenols and glucosamine fullerenes reduce infarct volume and cerebral inflammation after ischemic stroke in normotensive and hypertensive rats
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Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9
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The TLR3 ligand polyI:C downregulates connexin 43 expression and function in astrocytes by a mechanism involving the NF‐κB and PI3 kinase pathways
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“1) lend further support to the observation that ligands for TLR3 potently activate human astrocytes in vitro and in vivo (Jack et al., 2005; Farina et al., 2005; Town et al., 2006), and strongly implicate astrocytes as a major component of the innate immune response in the CNS, particularly as it…”
BackgroundResultInfluential
Immunotherapy of Malignant Tumors in the Brain: How Different from Other Sites?
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“As a consequence, poly-ICLC has been extensively tested in patients with glioma, with the reported induction of robust vaccine-specific CD8 T cell responses associated with detection of CXCL10 in the circulation (90, 91).”
Background
Cell Type–Specific Methylome-wide Association Studies Implicate Neurotrophin and Innate Immune Signaling in Major Depressive Disorder
Chan, R. F., Turecki, G., Shabalin, A. A., Guintivano, J., Zhao, M., Xie, L. Y., van Grootheest, G., Kaminsky, Z. A., Dean, B., Penninx, B. W. J. H., et al. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.10.014 · Cited by 61
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“Activated microglia have a wide variety of pattern recognition receptors from the Toll-like receptor group (TLR) that detect microbial intruders.(11) Thirteen types of TLR receptors have been identified in mammals and microglia express TLRs 1 through 9 at the very least.”
Glaucocalyxin B Alleviates Lipopolysaccharide-Induced Parkinson’s Disease by Inhibiting TLR/NF-κB and Activating Nrf2/HO-1 Pathway
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The majority of infiltrating CD8 T lymphocytes in multiple sclerosis lesions is insensitive to enhanced PD‐L1 levels on CNS cells
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“enhanced following their activation (Jack et al., 2005).”
The Potential of Mesenchymal Stromal Cells as a Novel Cellular Therapy for Multiple Sclerosis
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Intracellular expression of toll-like receptor 4 in neuroblastoma cells and their unresponsiveness to lipopolysaccharide
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“NB-1 cells do not express IRF-3 Among all TLRs, only TLR3 and TLR4 can induce cellular activation in both MyD88 dependent and independent pathway [21].”
BackgroundInfluential
Resveratrol Improves Neuroimmune Dysregulation Through the Inhibition of Neuronal Toll-Like Receptors and COX-2 Signaling in BTBR T+ Itpr3tf/J Mice
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“TLR2 ligands stimulate astrocytic and microglial cells leading to an upregulation in the production of cytokines and chemokines (Jack et al. 2005).”
Background
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“The CNS, as a vital organ, expresses all the known TLRs, mainly involving glial cells (microglia, astrocytes and oligodentrocytes) (Olson and Miller, 2004, Jack et al., 2005).”
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“Microglia show constitutive expression of virtually all TLRs, whereas astrocytes predominately express TLR3 and sometimes TLR2 [3,4,24].”
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“Like microglia, astrocytes also express functional TLRs, especially TLR3 and TLR4, and thus serve as sensitive innate immune effectors in brain [42] by secreting various pro-inflammatory cytokines in response to activation [43].”
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“TLR3 (Bsibsi et al., 2006; Jack et al., 2005).”
The role of Locus Coeruleus in neuroinflammation occurring in Alzheimer’s disease
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Role of glial cells in innate immunity and their role in CNS demyelination
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Cannabinoids and Innate Immunity: Taking a Toll on Neuroinflammation
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“Indeed, more recent studies have characterized TLR expression profiles on resident CNS cells, including microglia (TLRs 1–9)[22], astrocytes (TLRs 1–5, 9, 13)[23,24,25], and neurons (TLRs 2–5, 8, 9, 11–13)[24,26,27].”
Background
Mast cells in the autonomic nervous system and potential role in disorders with dysautonomia and neuroinflammation
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Regulation of Toll‐like receptor 4 expression and its signaling by hypoxia in cultured microglia
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“TLRs are also believed to participate in microglial activation in mice (Olson and Miller, 2004) and humans (Jack et al., 2005).”
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Mendelian predisposition to herpes simplex encephalitis
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Paeonol Suppresses Neuroinflammatory Responses in LPS-Activated Microglia Cells
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Dual Effects of Human Placenta-Derived Neural Cells on Neuroprotection and the Inhibition of Neuroinflammation in a Rodent Model of Parkinson’s Disease
Kim, H. W., Lee, H., Kang, J. M., Bae, S., Kim, C., Lee, S., Schwarz, J., Kim, G. J., Kim, J.-S., Cha, D. H., et al. (2018) · Cell Transplantation · doi:10.1177/0963689718766324 · Cited by 50
“For detailed assessment, microglia cells were categorized into six subtypes according to their shapes, ovoid shape amoeboid (1), larger shape amoeboid (2), large lamellipodia (3), bipolar ramified (4), heterogeneous ramified (5) and multiple extend process (6).”
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T Cells—Protective or Pathogenic in Alzheimer’s Disease?
McManus, R. M., Mills, K. H. G., & Lynch, M. A. (2015) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-015-9612-2 · Cited by 54
Expression of TLR9 within human glioblastoma
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“(CD20+), pDCs and probably microglial cells which both express CD68 [4, 15–17].”
Background
Conditioned medium from relapsing-remitting multiple sclerosis patients reduces the expression and release of inflammatory cytokines induced by LPS-gingivalis in THP-1 and MO3.13 cell lines
Ballerini, P., Diomede, F., Petragnani, N., Cicchitti, S., Merciaro, I., Cavalcanti, M. F. X. B., & Trubiani, O. (2017) · Cytokine · doi:10.1016/j.cyto.2017.04.022 · Cited by 49
Toll-Like Receptors in CNS Viral Infections
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“TLR3 expression has been shown to be uniquely upregulated by many stimuli (Farina et al. 2005; Jack et al. 2005; Bsibsi et al. 2006; Suh et al. 2007).”
Influential

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)
ORCID: Jack, Carolyn S
Arbour, Nathalie
Shapiro, Aaron
Antel, Jack P
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
DOI: 10.4049/jimmunol.175.7.4320
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
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
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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TLR Signaling Tailors Innate Immune Responses in Human Microglia and Astrocytes

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