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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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“Microglia express most TLRs, and their expression levels are altered by microglial activation [252].”
BackgroundAntigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain
Becher, B., Bechmann, I., & Greter, M. (2006) · Journal of Molecular Medicine · doi:10.1007/s00109-006-0065-1 · Cited by 236
“, CD80, CD86, CD40, ICAM-1, and VCAM-1) upon exposure to IFNγ [106] and are capable of sensing pathogens through toll-like receptors [107].”
BackgroundThe mechanisms of microgliosis and pain following peripheral nerve injury
Calvo, M., & Bennett, D. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.08.018 · Cited by 227
“Microglia express the TLRs 1 to 9 (Jack et al., 2005; Olson and Miller, 2004).”
BackgroundmiR‐155 as a multiple sclerosis–relevant regulator of myeloid cell polarization
Moore, C. S., Rao, V. T. S., Durafourt, B. A., Bedell, B. J., Ludwin, S. K., Bar‐Or, A., & Antel, J. P. (2013) · Annals of Neurology · doi:10.1002/ana.23967 · Cited by 219
Self-citationLong‐COVID syndrome‐associated brain fog and chemofog: Luteolin to the rescue
Theoharides, T. C., Cholevas, C., Polyzoidis, K. S., & Politis, A. M. (2021) · BioFactors · doi:10.1002/biof.1726 · Cited by 227
Antidepressant therapies inhibit inflammation and microglial M1-polarization
Kalkman, H. O., & Feuerbach, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.001 · Cited by 212
Lund, S., Christensen, K. V., Hedtjärn, M., Mortensen, A. L., Hagberg, H., Falsig, J., Hasseldam, H., Schrattenholz, A. S., Pörzgen, P., & Leist, M. (2006) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.07.007 · Cited by 217
“Microglia are equipped with a broad range of pattern-recognition receptors of the toll-like receptor family (TLR family) to detect microbial intruders (Jack et al., 2005).”
BackgroundTang, S.-C., Lathia, J. D., Selvaraj, P. K., Jo, D.-G., Mughal, M. R., Cheng, A., Siler, D. A., Markesbery, W. R., Arumugam, T. V., & Mattson, M. P. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.05.014 · Cited by 232
“Some TLRs are present in the brain, where their expression where they are expressed in glial cells (microglia, astrocytes and oligodentrocytes) (Lehnardt et al., 2003; Olson and Miller., 2004; Jack et al., 2005; Walter et al., 2007) and neurons (Lefon et al.”
BackgroundThe Interleukin-10 Family of Cytokines and Their Role in the CNS
Burmeister, A. R., & Marriott, I. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00458 · Cited by 217
“It is clear that both microglia and astrocytes can be a source of IL-10, and that they are responsive to the immunosuppressive actions of this cytokine (Jack et al., 2005; Bsibsi et al., 2006; Rasley et al., 2006; Park et al., 2007; Gautam et al., 2011; Gutierrez-Murgas et al., 2016).”
BackgroundCarpentier, A. C., Métellus, P., Ursu, R., Zohar, S., Lafitte, F., Barrié, M., Meng, Y., Richard, M., Parizot, C., Laigle–Donadey, F., et al. (2010) · Neuro-Oncology · doi:10.1093/neuonc/nop047 · Cited by 204
Toll-like receptors and their role in persistent pain
Lacagnina, M. J., Watkins, L. R., & Grace, P. M. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.10.006 · Cited by 216
“In addition to DRGs, these endosomal-residing TLRs are thought to be expressed in varying degrees on microglia, astrocytes, oligodendrocytes, Schwann cells, fibroblasts, endothelial cells (Bsibsi et al., 2002; Goethals et al., 2010; Jack et al., 2005; Lehmann et al., 2012; Olson & Miller, 2004).”
Immune Players in the CNS: The Astrocyte
Jensen, C., Massie, A., & Keyser, J. D. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9480-6 · Cited by 216
Domínguez-Punaro, M. D. L. C., Segura, M., Plante, M.-M., Lacouture, S., Rivest, S., & Gottschalk, M. G. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.3.1842 · Cited by 200
“Both types of cells express constitutively low levels of mRNA encoding different TLRs which can be notably increased following the binding of specific ligands (23, 24).”
BackgroundInnate Immunity and Neuroinflammation
Shastri, A., Bonifati, D. M., & Kishore, U. (2013) · Mediators of Inflammation · doi:10.1155/2013/342931 · Cited by 207
“IFN-𝛽 therapy is effective in treating inflammasome-dependent disease in mouse models of MS [159].”
BackgroundOspelt, C., & Gay, S. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.10.010 · Cited by 198
Ifergan, I., Kébir, H., Bernard, M., Wosik, K., Dodelet-Devillers, A., Cayrol, R., Arbour, N., & Prat, A. (2007) · Brain · doi:10.1093/brain/awm295 · Cited by 199
Multiple Sclerosis and T Lymphocytes: An Entangled Story
Legroux, L., & Arbour, N. (2015) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-015-9614-0 · Cited by 206
“, IL-6, IL-12, IL-23, TNF) (Jack et al. 2005; Strachan-Whaley et al. 2014); although the cytokine levels produced by activated microglia can be lower than those produced by macrophages (Wlodarczyk et al.”
BackgroundZhu, X., Nishimura, F., Sasaki, K., Fujita, M., Dusak, J. E., Eguchi, J., Fellows-Mayle, W. K., Storkus, W. J., Walker, P. R., Salazar, A. Μ., et al. (2007) · Journal of Translational Medicine · doi:10.1186/1479-5876-5-10 · Cited by 194
“In the CNS and CNS tumors, recent studies have reported that both microglia [13] and astrocytes express TLR3 [3,14].”
BackgroundTurco, F., Sarnelli, G., Cirillo, C., Palumbo, I., Giorgi, F. D., D’Alessandro, A., Cammarota, M., Giuliano, M., & Cuomo, R. (2013) · Gut · doi:10.1136/gutjnl-2012-302090 · Cited by 193
Alvarado, A. G., Thiagarajan, P. S., Mulkearns-Hubert, E. E., Silver, D. J., Hale, J. S., Alban, T. J., Turaga, S. M., Jarrar, A., Reizes, O., Longworth, M. S., et al. (2017) · Cell stem cell · doi:10.1016/j.stem.2016.12.001 · Cited by 188
“The brain has a distinct set of immune regulatory mechanisms, and diverse TLR expression in neurons, astrocytes, oligodendrocytes, and microglia contributes to normal brain function and homeostasis (Jack et al., 2005; Okun et al., 2009; van Noort and Bsibsi, 2009).”
Toll-Like Receptor 2 Signaling in Response to Brain Injury: An Innate Bridge to Neuroinflammation
Babcock, A. A., Wirenfeldt, M., Holm, T. H., Nielsen, H. H., Dissing‐Olesen, L., Toft‐Hansen, H., Millward, J. M., Landmann, R. M., Rivest, S., Finsen, B. R., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.4937-05.2006 · Cited by 188
“Both astrocytes and microglia have been shown to express TLRs in vitro (Olson and Miller, 2004; Carpentier et al., 2005; Jack et al., 2005).”
BackgroundImmune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids
Bartok, E., & Hartmann, G. (2020) · Immunity · doi:10.1016/j.immuni.2020.06.014 · Cited by 190
Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection.
Clark, K. H., Wiley, C. A., & Bradberry, C. W. (2013) · Neurotoxicity Research · doi:10.1007/s12640-012-9334-7 · Cited by 194
The Innate Immune Facet of Brain: Human Neurons Express TLR-3 and Sense Viral dsRNA
Lafon, M., Mégret, F., Lafage, M., & Prehaud, C. J. N. (2006) · Journal of Molecular Neuroscience · doi:10.1385/jmn:29:3:185 · Cited by 183
TLR3 immunity to infection in mice and humans
Zhang, S., Casadio, M., Ciancanelli, M. J., de Diego, R. P., Sancho‐Shimizu, V., Abel, L., & Casanova, J. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.11.001 · Cited by 178
Rossi, D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.04.003 · Cited by 185
Glial toll-like receptor signaling in central nervous system infection and autoimmunity
Carpentier, P. A., Duncan, D. S., & Miller, S. D. (2007) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2007.08.011 · Cited by 178
“To date, human astrocytes have been reported to express TLRs1-5 and TLR9, also with particularly high expression of TLR3 (Bsibsi et al., 2006; Bsibsi et al., 2002; Jack et al., 2005).”
BackgroundHaslund‐Vinding, J., McBean, G., Jaquet, V, & Vilhardt, F. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13425 · Cited by 169
Microglia Activation and Anti-inflammatory Regulation in Alzheimer’s Disease
Lue, L., Kuo, Y., Beach, T. G., & Walker, D. G. (2010) · Molecular Neurobiology · doi:10.1007/s12035-010-8106-8 · Cited by 173
“They react to these conditions by changing motility, shape of processes and cell bodies, phagocytic functions, releases of cytokines, chemokines, reactive oxygen species and prostaglandin metabolites, and expression of innate and adaptive immunefunction molecules [13, 18–20].”
Pais, T. F., Szegő, É. M., Marques, O., Miller‐Fleming, L., Antas, P., Guerreiro, P. S., de Oliveira, R. M., Kasapoğlu, B., & Outeiro, T. F. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.200 · Cited by 177
“We analysed several established activation markers, including IL-10 production, which is induced following TLR ligation in microglia (Jack et al , 2005).”
Toll-like Receptors in Defense and Damage of the Central Nervous System
Aravalli, R. N., Peterson, P. K., & Lokensgard, J. R. (2007) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-007-9071-5 · Cited by 173
“In fact, microglia have been reported to express mRNAs for TLRs 1–9 (Lee and Lee 2002; Olson and Miller 2004; Jack et al. 2005; McKimmie and Fazakerley 2005; Jung et al. 2005), whereas neurons (Prehaud et al.”
BackgroundReinert, L. S., Harder, L., Holm, C. K., Iversen, M. B., Horan, K., Dagnæs‐Hansen, F., Ulhøi, B. P., Holm, T. H., Mogensen, T. H., Owens, T., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60893 · Cited by 171
“Since, TLR3 is reported to be highly expressed by astrocytes (30–33), we focused on this cell type.”
Role of ninjurin‐1 in the migration of myeloid cells to central nervous system inflammatory lesions
Ifergan, I., Kébir, H., Terouz, S., Alvarez, J. I., Lécuyer, M., Gendron, S., Bourbonnière, L., Dunay, I. R., Bouthillier, A., Moumdjian, R. A., et al. (2011) · Annals of Neurology · doi:10.1002/ana.22519 · Cited by 167
Anti-inflammatory Effects of Curcumin in Microglial Cells
Yu, Y., Shen, Q., Lai, Y., Park, S. Y., Ou, X., Lin, D., Jin, M., & Zhang, W. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00386 · Cited by 166
“Microglia express pattern recognition receptors (PRR) that can bind to pattern-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), respectively (Jack et al., 2005).”
BackgroundMicroglia and Astrocyte Function and Communication: What Do We Know in Humans?
Garland, E. F., Hartnell, I. J., & Boche, D. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.824888 · Cited by 165
Human Toll‐like receptor‐dependent induction of interferons in protective immunity to viruses
Zhang, S., Jouanguy, E., Sancho‐Shimizu, V., von Bernuth, H., Yang, K., Abel, L., Pïcard, C., Puel, A., & Casanova, J. (2007) · Immunological Reviews · doi:10.1111/j.1600-065x.2007.00564.x · Cited by 171
“Many in vitro studies have shown that a functional TLR3 is expressed in these cell types, which produce IFN-a, -b, -l and other cytokines and chemokines in response to poly(I:C) stimulation, presumably via TLR3 (68, 112, 113, 115, 118, 119, 121) .”
BackgroundGlial influences on BBB functions and molecular players in immune cell trafficking
Lécuyer, M., Kébir, H., & Prat, A. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.10.004 · Cited by 166
Ronaldson, P. T., & Davis, T. P. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212802002625 · Cited by 160
Toll‐like receptor expression in the peripheral nerve
Goethals, S., Ydens, E., Timmerman, V., & Janssens, S. (2010) · Glia · doi:10.1002/glia.21041 · Cited by 162
“In the nervous system, especially microglial cells appear to express a broad range of TLRs and as such are endowed with a sentinel function in the brain (Bsibsi et al., 2002; Jack et al., 2005; Olson and Miller, 2004).”
BackgroundMicroglial activation in the pathogenesis of Huntington's disease
Yang, H.-M., Yang, S., Huang, S.-S., Tang, B.-S., & Guo, J.-F. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00193 · Cited by 151
“TLR-2 is the most expressed TLR in microglia, which is responsible for IL-6 and IL-10 secretion.”
BackgroundInfluentialToll-Like Receptor 3 (TLR3) Plays a Major Role in the Formation of Rabies Virus Negri Bodies
Ménager, P., Roux, P., Mégret, F., Bourgeois, J., Sourd, A. L., Danckaert, A., Lafage, M., Prehaud, C. J. N., & Lafon, M. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000315 · Cited by 152
“High levels of TLR3 are found in glial cells [15,16] and neurons in”
BackgroundToll-like receptor 2, 3, and 4 expression and function in human airway smooth muscle
Sukkar, M. B., Xie, S., Khorasani, N. M., Kon, O. M., Stanbridge, R. D. L., Issa, R., & Chung, K. F. (2006) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2006.05.013 · Cited by 157
Crowley, T., Cryan, J. F., Downer, E. J., & O’Leary, O. F. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.02.001 · Cited by 150
“…resident CNS cells continues to be elucidated, with complements of receptors expressed on microglia (TLRs 1-9) (Aravalli et al., 2007; Jack et al., 2005), astrocytes (TLRs 1-5, 9) (Jack et al., 2005; Mishra et al., 2008), and neurons (TLRs 2-5, 8, 9, 11-12) (Ma et al., 2006; Mishra et al., 2008).”
BackgroundDysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation
Chu, E., Mychasiuk, R., Hibbs, M. L., & Semple, B. D. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02325-6 · Cited by 152
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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