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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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Cites
The Danger Model: A Renewed Sense of Self
Matzinger, P. (2002) · Science · doi:10.1126/science.1071059 · Cited by 4,205
Toll-like receptor control of the adaptive immune responses
Iwasaki, A., & Medzhitov, R. M. (2004) · Nature Immunology · doi:10.1038/ni1112 · Cited by 4,166
Takeda, K., & Akira, S. (2004) · Seminars in Immunology · doi:10.1016/j.smim.2003.10.003 · Cited by 2,528
Decoding the Patterns of Self and Nonself by the Innate Immune System
Medzhitov, R., & Janeway, C. A. (2002) · Science · doi:10.1126/science.1068883 · Cited by 2,154
Dendritic-cell control of pathogen-driven T-cell polarization
Kapsenberg, M. L. (2003) · Nature reviews. Immunology · doi:10.1038/nri1246 · Cited by 1,495
Inferences, questions and possibilities in Toll-like receptor signalling
Beutler, B. (2004) · Nature · doi:10.1038/nature02761 · Cited by 1,476
Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs
Olson, J. K., & Miller, S. D. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.6.3916 · Cited by 1,215
LPS-TLR4 Signaling to IRF-3/7 and NF-κB Involves the Toll Adapters TRAM and TRIF
Fitzgerald, K. A., Rowe, D. C., Barnes, B. J., Caffrey, D. R., Visintin, A., Latz, E., Monks, B. G., Pitha, P. M., & Golenbock, D. T. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20031023 · Cited by 1,193
Relapsing and remitting multiple sclerosis: Pathology of the newly forming lesion
Barnett, M. H., & Prineas, J. W. (2004) · Annals of Neurology · doi:10.1002/ana.20016 · Cited by 1,184
mRNA is an endogenous ligand for toll-like receptor 3
Karikó, K., Ni, H., Capodici, J., Lamphier, M., & Weissman, D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310175200 · Cited by 1,062
Broad Expression of Toll-Like Receptors in the Human Central Nervous System
Bsibsi, M., Ravid, R., Gveric, D. O., & van Noort, J. M. (2002) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/61.11.1013 · Cited by 1,000
Subcellular Localization of Toll-Like Receptor 3 in Human Dendritic Cells
Matsumoto, M., Funami, K., Tanabe, M., Oshiumi, H., Shingai, M., Seto, Y., Yamamoto, A., & Seya, T. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.6.3154 · Cited by 723
Goverman, J. M., Woods, A., Larson, L., Weiner, L. P., Hood, L., & Zaller, D. M. (1993) · Cell · doi:10.1016/0092-8674(93)90074-z · Cited by 684
Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells
Visintin, A., Mazzoni, A., Spitzer, J. H., Wyllie, D. H., Dower, S., & Segal, D. M. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.1.249 · Cited by 611
Boonstra, A., Asselin‐Paturel, C., Gilliet, M. F., Crain, C., Trinchieri, G., Liu, Y.-J., & O’Garra, A. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021908 · Cited by 566
Toll-like receptor 2 as a major gene for asthma in children of European farmers
Eder, W., Klimecki, W. J., Yu, L., von Mutius, E., Riedler, J., Braun‐Fahrländer, C., Nowak, D., & Martínez, F. D. (2004) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2003.12.374 · Cited by 509
Dillon, S. M., Agrawal, A., Dyke, T. E. V., Landreth, G. E., McCauley, L. K., Koh, A. J., Maliszewski, C. R., Akira, S., & Pulendran, B. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.8.4733 · Cited by 469
Redecke, V., Häcker, H., Datta, S. K., Fermin, A., Pitha, P. M., Broide, D. H., & Raz, E. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.5.2739 · Cited by 448
Differential activation of astrocytes by innate and adaptive immune stimuli
Carpentier, P. A., Begolka, W. S., Olson, J. K., Elhofy, A., Karpus, W. J., & Miller, S. D. (2004) · Glia · doi:10.1002/glia.20117 · Cited by 368
Toll-like receptors and dendritic cells: for whom the bug tolls
Sousa, C. R. E. (2004) · Seminars in Immunology · doi:10.1016/j.smim.2003.10.004 · Cited by 341
Molecular insights on the cerebral innate immune system
Rivest, S. (2003) · Brain, Behavior, and Immunity · doi:10.1016/s0889-1591(02)00055-7 · Cited by 338
Of mice and men: species variations of Toll-like receptor expression
Rehli, M. (2002) · Trends in Immunology · doi:10.1016/s1471-4906(02)02259-7 · Cited by 323
Influence of infection on exacerbations of multiple sclerosis
PANITCH, H. S. (1994) · Annals of Neurology · doi:10.1002/ana.410360709 · Cited by 276
Preferential expression and function of Toll-like receptor 3 in human astrocytes
Farina, C., Krumbholz, M., Giese, T., Hartmann, G., Aloisi, F., & Meinl, E. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.09.009 · Cited by 256
Protocols for Neural Cell Culture
FEDOROFF, S., & Richardson, A. K. (1993) · Trends in Neurosciences · doi:10.1016/0166-2236(93)90164-h · Cited by 249
Species-specific Regulation of Toll-like Receptor 3 Genes in Men and Mice
Heinz, S., Haehnel, V., Karaghiosoff, M., Schwarzfischer, L., Müller, M., Krause, S. W., & Rehli, M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301476200 · Cited by 202
PPAR ? agonists stimulate oligodendrocyte differentiation in tissue culture
Saluja, I., Granneman, J. G., & Skoff, R. P. (2001) · Glia · doi:10.1002/1098-1136(200103)33:3 · Cited by 186
DSouza, S., Alinauskas, K. A., McCrea, E., Goodyer, C. G., & Antel, J. P. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-11-07293.1995 · Cited by 180
Adib‐Conquy, M., & Cavaillon, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200705200 · Cited by 144
Bacterial peptidoglycan and immune reactivity in the central nervous system in multiple sclerosis
Schrijver, I. A. (2001) · Brain · doi:10.1093/brain/124.8.1544 · Cited by 139
Kielian, T., Mayes, P. M., & Kielian, M. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00216-3 · Cited by 129
Pisegna, S., Pirozzi, G., Piccoli, M., Frati, L., Santoni, A., & Palmieri, G. (2004) · Blood · doi:10.1182/blood-2004-05-1860 · Cited by 120
Visser, L. H., de Heer, H. J., Boven, L. A., van Riel, D. A. J., van Meurs, M., Melief, M., Zähringer, U., van Strijp, J. A. G., Lambrecht, B. N., Nieuwenhuis, E. E. S., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.2.808 · Cited by 119
Jotwani, R., Pulendran, B., Agrawal, S., & Cutler, C. W. (2003) · European Journal of Immunology · doi:10.1002/eji.200324392 · Cited by 112
Relapsing-Remitting Multiple Sclerosis and Human Herpesvirus 6 Active Infection
Álvarez‐Lafuente, R., Heras, V. D. L., Bartolomé, M., Picazo, J. J., & Arroyo, R. (2004) · Archives of Neurology · doi:10.1001/archneur.61.10.1523 · Cited by 111
Nagai, T., Devergne, O., Mueller, T., Perkins, D. L., van Seventer, J. M., & van Seventer, G. A. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.10.5233 · Cited by 105
Lipoprotein I, a TLR2/4 Ligand Modulates Th2-Driven Allergic Immune Responses
Revets, H., Pynaert, G., Grooten, J., & BAETSELIER, P. D. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.2.1097 · Cited by 102
Amyloid precursor protein (APP) expression in multiple sclerosis lesions
Gehrmann, J., Banati, R. B., Cuzner, M. L., Kreutzberg, G. W., & Newcombe, J. (1995) · Glia · doi:10.1002/glia.440150206 · Cited by 96
Becher, B., Dodelet, V. C., Fedorowicz, V. J., & Antel, J. P. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118946 · Cited by 94
Astrocytes in chronic active multiple sclerosis plaques express MHC class II molecules
Zeinstra, E., Wilczak, N., Streefland, C., & Keyser, J. D. (2000) · Neuroreport · doi:10.1097/00001756-200001170-00018 · Cited by 87
Zeinstra, E. M. P. E., Wilczak, N., & Keyser, J. D. (2003) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00462-9 · Cited by 83
Culture of Glial Cells from Human Brain Biopsies
Yong, V. W., & Antel, J. P. (1997) · Humana Press eBooks · doi:10.1007/978-1-4757-2586-5_11 · Cited by 71
Contini, C., Cultrera, R., Seraceni, S., Castellazzi, M., Granieri, E., & Fainardi, E. (2004) · Multiple Sclerosis Journal · doi:10.1191/1352458504ms1049oa · Cited by 35
Circumferential migration of ameboid microglia in the margin of the developing quail retina
Marín‐Teva, J. L., Calvente, R., Cuadros, M. Á., Almendros, A., & Navascués, J. (1999) · Glia · doi:10.1002/(sici)1098-1136(199909)27:3 · Cited by 26
Human brain endothelial cells supply support for monocyte immunoregulatory functions
Seguin, R. M., Moditi, Z., Rotondo, R. L., Biernacki, K., Wosik, K., Prat, A., & Antel, J. P. (2003) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00431-9 · Cited by 13
Zujovic (2000) · doi:10.1002/(sici)1098-1136(20000215)29:4
Flagged first, then by citations
Research works printed but not linked: 44
- 2004, Semin. Immunol., 27
- 2000, Glia, 293
- 2000, Neuroreport, 89
- 2003, J. Neuroimmunol., 166
- 1995, Glia, 141
- 2002, Science, 298
- 2002, Science, 301
- 1994, Ann. Neurol., S25
- 2004, Arch. Neurol., 1523
- 2004, Ann. Neurol., 458
- 2004, Mult. Scler., 360
- 2004, Nature, 257
- 2004, Nat. Immunol., 987
- 2004, Semin. Immunol., 3
- 2003, J. Exp. Med., 1043
- 2005, J. Immunol., 1097
- 2002, Trends Immunol., 375
- 2003, J Biol. Chem., 21502
- 2005, Glia, 360
- 2001, J. Immunol., 249
- 2004, J. Immunol., 3916
- 2002, J. Neuropathol. Exp. Neurol., 1013
- 1999, Glia, 259
- 1995, J. Neurosci., 7293
- 2001, Glia, 217
- 2003, J. Neuroimmunol., 96
- 2005, J. Neuroimmunol., 12
- 2002, J. Neuroimmunol., 86
- 2001, Brain, 1544
- 2003, J. Immunol., 3154
- 2004, J. Biol. Chem., 12542
- 2004, J. Immunol., 2739
- 2003, Eur. J. Immunol., 2980
- 2004, J. Allergy Clin. Immunol., 482
- 2004, J. Immunol., 4733
- 2004, Blood, 4157
- 2003, J. Immunol., 5233
- 1996, J. Clin. Invest., 1539
- 2003, Nat. Rev. Immunol., 984
- 2003, J. Exp. Med., 101
- 2002, J. Biol. Chem., 27927
- 2005, J. Immunol., 808
- 1993, Cell, 551
- 2003, Brain Behav. Immun., 13
Cited by
Sorted by citations
Glutamate neurotoxicity and diseases of the nervous system
Choi, D. W. (1988) · Neuron · doi:10.1016/0896-6273(88)90162-6 · Cited by 8,188
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Block, M. L., Zecca, L., & Hong, J.-S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2038 · Cited by 4,110
Kettenmann, H., Hanisch, U.-K., Noda, M., & Verkhratsky, A. (2011) · Physiological Reviews · doi:10.1152/physrev.00011.2010 · Cited by 3,547
Verkhratsky, A., & Nedergaard, M. (2018) · Physiological Reviews · doi:10.1152/physrev.00042.2016 · Cited by 1,678
“In human astrocytes expression of a TLR1 5 and TLR9 has been reported (250, 779); of these TLR2 4 were identified also in vivo, especially in pathological conditions (250, 779, 1695).”
Rothhammer, V., Mascanfroni, I. D., Bunse, L., Takenaka, M. C., Kenison, J. E., Mayo, L., Chao, C.-C., Patel, B., Yan, R., Blain, M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4106 · Cited by 1,559
“Human fetal astrocytes were isolated as previously described 11,63 from human CNS tissue from fetuses at 17–23 weeks of gestation obtained from the Human Fetal Tissue Repository (Albert Einstein College of Medicine) following Canadian Institutes of Health Research– approved guidelines.”
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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