Toll‐like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram‐negative bacterial cell wall components
Abstract
The recent characterization of human homologues of Toll may be the missing link for the transduction events leading to NF‐κB activity and proinflammatory gene transcription during innate immune response. Indeed, CD14 is not thought to participate directly in the cell signaling, but rather one or more of the mammalian Toll‐like receptors (TLRs) acts in concert with the lipopolysaccharide (LPS) receptor to discriminate between microbial pathogens or their products and initiate transmembrane signaling. Mammalian cells may express as many as 10 distinct TLRs, although the importance of TLR4 in response to gramnegative bacteria and LPS is now supported by the fact that TLR4‐mutated mice are LPS resistant. We investigated the expression of TLR4 across the rat brain under basal conditions and in response to systemic LPS and IL‐1ß injection. We first cloned the rat TLR4 cDNA via RNA isolation and polymerase chain reaction (PCR) amplification with a proofreading polymerase. Total RNA was isolated from the rat liver tissue using Tri‐Reagent and reverse transcribed into cDNA using Superscript II reverse transcriptase and an oligonucleotide primer with a degenerate 3' end of sequence 5'‐T12(GAC)N‐3'. Positive hybridization signal was found in the leptomeninges, choroid plexus (chp), subfornical organ, organum vasculosum of the lamina terminalis, median eminence, and area postrema. Scattered small cells also displayed a convincing hybridization signal within the brain parenchyma. Few well‐defined nuclei exhibited positive TLR4 transcript: the supramamillary nucleus, cochlear nucleus, and the lateral reticular nucleus. The circumventricular organs, the leptomeninges, and chp also exhibited constitutive expression of the LPS receptor mCD14. In contrast to the strong up‐regulation of the gene encoding mCD14 during endotoxemia, neither LPS nor IL‐1β caused a convincing increase in the TLR4 mRNA levels across the CNS. A down‐regulation of the gene encoding TLR4 was found in the cerebral tissue of immune‐challenged animals. The constitutive expression of both mCD14 and TLR4 may explain the innate immune response in the brain, which originates from the structures devoid of blood‐brain barrier in presence of circulating LPS.—Laflamme, N., Rivest, S. Toll‐like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram‐negative bacterial cell wall components. FASEB J. 15, 155–163 (2001)
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CVOs and other CNS barrier tissues can respond to various inflammatory stimuli through expression of cytokine receptors, Toll-like receptors (TLRs), and CD14.
“CVOs and other CNS barrier tissues can, in turn, respond to various inflammatory stimuli through expression of cytokine receptors (103), Toll-like receptors (TLRs) (104), and CD14 (105).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [104]
Cites
CD14, a Receptor for Complexes of Lipopolysaccharide (LPS) and LPS Binding Protein
Wright, S. D., Ramos, R., Tobias, P. S., Ulevitch, R. J., & Mathison, J. C. (1990) · Science · doi:10.1126/science.1698311 · Cited by 3,986 · see citing works
Takeuchi, O., Hoshino, K., Kawai, T., Sanjo, H., Takada, H., Ogawa, T., Takeda, K., & Akira, S. (1999) · Immunity · doi:10.1016/s1074-7613(00)80119-3 · Cited by 3,680 · see citing works
Unresponsiveness of MyD88-deficient mice to endotoxin.
Kawai, T., Adachi, O., Ogawa, T., Takeda, K., & Akira, S. (1999) · Immunity · doi:10.1016/s1074-7613(00)80086-2 · Cited by 2,367 · see citing works
Tlr4: central component of the sole mammalian LPS sensor.
Beutler, B. (2000) · Current Opinion in Immunology · doi:10.1016/s0952-7915(99)00046-1 · Cited by 847 · see citing works
Nomura, F., Akashi, S., Sakao, Y., Sato, S., Kawai, T., Matsumoto, M., Nakanishi, K., Kimoto, M., Miyake, K., Takeda, K., et al. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.7.3476 · Cited by 765 · see citing works
Haziot, A., Ferrero, E., Köntgen, F., Hijiya, N., Yamamoto, S., Silver, J. E., Stewart, C. L., & Goyert, S. M. (1996) · Immunity · doi:10.1016/s1074-7613(00)80254-x · Cited by 732 · see citing works
Toll signaling pathways in the innate immune response.
Anderson, K. V. (2000) · Current Opinion in Immunology · doi:10.1016/s0952-7915(99)00045-x · Cited by 677 · see citing works
Quan, N., Whiteside, M., & Herkenham, M. (1998) · Neuroscience · doi:10.1016/s0306-4522(97)00350-3 · Cited by 335 · see citing works
Vallières, L., & Rivest, S. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69041668.x · Cited by 323 · see citing works
Self-citationLaflamme, N., Lacroix, S., & Rivest, S. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-24-10923.1999 · Cited by 287 · see citing works
Self-citationToll, A New Piece in the Puzzle of Innate Immunity
Wright, S. D. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.189.4.605 · Cited by 235 · see citing works
Lacroix, S., Feinstein, D., & Rivest, S. (1998) · Brain Pathology · doi:10.1111/j.1750-3639.1998.tb00189.x · Cited by 223 · see citing works
Self-citationPerera, P., Vogel, S. N., Detore, G. R., Haziot, A., & Goyert, S. M. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.9.4422 · Cited by 220 · see citing works
Nadeau, S., & Rivest, S. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-09-03456.2000 · Cited by 217 · see citing works
Self-citationLaflamme, N., & Rivest, S. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0730309.x · Cited by 182 · see citing works
Self-citationMuzio, M., Polentarutti, N., Bosisio, D., Prahladan, M. K. P., & Mantovani, A. (2000) · Journal of Leukocyte Biology · doi:10.1002/jlb.67.4.450 · Cited by 176 · see citing works
Bacterial Toxin‐Induced Cytokine Production Studied at the Single‐Cell Level
Andersson, J., Nagy-Agren, S. E., Bjourk, L., Abrams, J. S., Holm, S. E., & Andersson, U. (1992) · Immunological Reviews · doi:10.1111/j.1600-065x.1992.tb01409.x · Cited by 159 · see citing works
Nadeau, S., & Rivest, S. (1999) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199901000-00008 · Cited by 142 · cited 3× · see citing works
“Microscopic analysis of emulsion-dipped slides revealed that TNFpositive cells spread over the anatomical boundaries of the CVOs in a migratory-like pattern during the course of the endotoxemia ( 14 ).”
BackgroundInfluentialSelf-citation
Flagged first, then by citations
Cited by
Sorted by citations
TLR4 links innate immunity and fatty acid-induced insulin resistance
Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., & Flier, J. S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28898 · Cited by 3,690 · see citing works
Astrocytes are active players in cerebral innate immunity
Farina, C., Aloisi, F., & Meinl, E. (2007) · Trends in Immunology · doi:10.1016/j.it.2007.01.005 · Cited by 1,304 · see citing works
Visceral influences on brain and behavior
Critchley, H. D., & Harrison, N. A. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.008 · Cited by 1,177 · see citing works
Lehnardt, S., Massillon, L., Follett, P., Jensen, F. E., Ratan, R., Rosenberg, P. A., Volpe, J. J., & Vartanian, T. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1432609100 · Cited by 1,052 · see citing works
The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy
Tanga, F. Y., Nutile-McMenemy, N., & DeLeo, J. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501634102 · Cited by 634 · see citing works
Inefficient clearance of myelin debris by microglia impairs remyelinating processes
Lampron, A., Larochelle, A., Laflamme, N., Préfontaine, P., Plante, M.-M., Sánchez, M. G., Yong, V. W., Stys, P. K., Tremblay, M.-È., & Rivest, S. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20141656 · Cited by 595 · see citing works
Pattern recognition receptors and central nervous system repair
Kigerl, K. A., de Rivero Vaccari, J. P., Dietrich, W. D., Popovich, P. G., & Keane, R. W. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.01.001 · Cited by 490 · see citing works
Chakravarty, S., & Herkenham, M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4268-04.2005 · Cited by 396 · see citing works
Neuroimmune activation and neuroinflammation in chronic pain and opioid tolerance/hyperalgesia
Deleo, J. A., Tanga, F. Y., & Tawfik, V. L. (2004) · The Neuroscientist · doi:10.1177/1073858403259950 · Cited by 371 · see citing works
Neuroprotective role of the innate immune system by microglia
Glezer, I., Simard, A. R., & Rivest, S. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.02.055 · Cited by 371 · see citing works
Self-citationThe anatomy and immunology of vasculature in the central nervous system
Mastorakos, P., & McGavern, D. (2019) · Science Immunology · doi:10.1126/sciimmunol.aav0492 · Cited by 333 · see citing works
The LPS receptor (CD14) links innate immunity with Alzheimer's disease
Fassbender, K., Walter, S., Kühl, S., Landmann, R., Ishii, K., Bertsch, T., Stalder, A. K., Muehlhauser, F., Liu, Y., Ulmer, A. J., et al. (2004) · The FASEB Journal · doi:10.1096/fj.03-0364fje · Cited by 307 · see citing works
Self-citationRole of Microglia TLRs in Neurodegeneration
Fiebich, B. L., Batista, C. R. A., Saliba, S. W., Yousif, N. M., & de Oliveira, A. C. P. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00329 · Cited by 291 · see citing works
Autonomic neural regulation of immunity
CZURA, C. J., & TRACEY, K. J. (2005) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2004.01442.x · Cited by 255 · see citing works
Dual Roles for Perivascular Macrophages in Immune-to-Brain Signaling
Serrats, J., Schiltz, J. C., García-Bueno, B., van Rooijen, N., Reyes, T. M., & Sawchenko, P. E. (2010) · Neuron · doi:10.1016/j.neuron.2009.11.032 · Cited by 253 · see citing works
Gereben, B., Zeöld, A., Dentice, M., Salvatore, D., & Bianco, A. C. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7396-0 · Cited by 207 · see citing works
Naert, G., & Rivest, S. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.0299-11.2011 · Cited by 207 · see citing works
“Dual labeling combining immunocytochemistry and in situ hybridization was performed as described previously (Nadeau and Rivest, 2000; Laflamme and Rivest, 2001) to detect CX3CR1, TGF- 1, TGF- R1, and TGF- R2 transcripts in microglia (iba-1 -staining).”
MethodSinghrao, S. K., Harding, A., Poole, S., Kesavalu, L., & Crean, S. (2015) · Mediators of Inflammation · doi:10.1155/2015/137357 · Cited by 195 · see citing works
Fekete, C., Gereben, B., Doleschall, M., Harney, J. W., Dora, J. M., Bianco, A. C., Sarkar, S., Liposits, Z., Rand, W., Emerson, C., et al. (2004) · Endocrinology · doi:10.1210/en.2003-1439 · Cited by 179 · see citing works
Polyunsaturated fatty acids, neuroinflammation and well being
Layé, S. (2010) · Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA) · doi:10.1016/j.plefa.2010.02.006 · Cited by 167 · see citing works
Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease
Noelker, C., Morel, L., Lescot, T., Osterloh, A., Alvarez-Fischer, D., Breloer, M., Henze, C., Depboylu, C., Skrzydelski, D., Michel, P. P., et al. (2013) · Scientific Reports · doi:10.1038/srep01393 · Cited by 164 · see citing works
The choroid plexus—a multi-role player during infectious diseases of the CNS
Schwerk, C., Tenenbaum, T., Kim, K. S., & Schroten, H. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00080 · Cited by 147 · see citing works
Hypothalamic inflammation and energy homeostasis: Resolving the paradox
Thaler, J. P., Choi, S. J., Schwartz, M. W., & Wisse, B. E. (2010) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.10.002 · Cited by 144 · see citing works
Kristensson, K., Nygård, M., Bertini, G., & Bentivoglio, M. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.12.001 · Cited by 140 · see citing works
Escames, G., Acuña-Castroviejo, D., López, L. C., Tan, D.-X., Maldonado, M. D., Sánchez-Hidalgo, M., León, J., & Reiter, R. J. (2006) · Journal of Pharmacy and Pharmacology · doi:10.1211/jpp.58.9.0001 · Cited by 118 · see citing works
Saha, S., Engström, L., Mackerlova, L., Jakobsson, P.-J., & Blomqvist, A. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00872.2004 · Cited by 108 · see citing works
Turrin, N. P., & Rivest, S. (2004) · Experimental Biology and Medicine · doi:10.1177/153537020422901003 · Cited by 107 · see citing works
Vegeto, E., Ghisletti, S., Meda, C., Etteri, S., Belcredito, S., & Maggi, A. (2004) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2004.02.004 · Cited by 103 · see citing works
Nadeau, S., & Rivest, S. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.6.3370 · Cited by 94 · see citing works
Characterization of the Nuclear Factor-κB Responsiveness of the Human dio2 Gene
Zeöld, A., Doleschall, M., Haffner, M. C., Capelo, L. P., Menyhért, J., Liposits, Z., da Silva, W. S., Bianco, A. C., Kacskovics, I., Fekete, C., et al. (2006) · Endocrinology · doi:10.1210/en.2005-1608 · Cited by 72 · see citing works
Glial functions in the blood-brain communication at the circumventricular organs
Miyata, S. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.991779 · Cited by 66 · see citing works
Furube, E., Morita, M., & Miyata, S. (2015) · Cell and Tissue Research · doi:10.1007/s00441-015-2201-0 · Cited by 47 · see citing works
Bowerman, M., Vincent, T., Scamps, F., Perrin, F. E., Camu, W., & Raoul, C. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00214 · Cited by 46 · see citing works
Zhang, A., Hao, S., Bi, J., Bao, Y., Zhang, X., An, L., & Jiang, B. (2009) · Experimental and Toxicologic Pathology · doi:10.1016/j.etp.2008.10.010 · Cited by 46 · see citing works
Knockdown of TLR4 represses the paraquat-induced neuroinflammation and microglial M1 polarization
Huang, M., Li, Y., Tian, T., Wang, K., Wang, Y., Yan, W., & Yang, H. (2020) · Neurotoxicity Research · doi:10.1007/s12640-020-00261-6 · Cited by 14 · see citing works
- Authors
- LAFLAMME, N., & RIVEST, S.
- Affiliations
- Centre hospitalier de l'Université Laval (CA)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2001-01
- Volume
- 15
- Issue
- 1
- Pages
- 155-163
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2107865650
- Cited by
- 501
- References
- 18
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 11 · 2023: 11 · 2022: 7 · 2021: 18 · 2020: 20 · 2019: 10 · 2018: 17 · 2017: 10 · 2016: 17 · 2015: 19 · 2014: 32 · 2013: 32 · 2012: 22
- FWCI
- 8.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada (MRCC)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TLR4, lipopolysaccharide, CD14, endotoxemia, IL-1β, circumventricular organs, choroid plexus, leptomeninges, TLR4 mRNA expression, NF-κB signaling, rat brain
- MeSH terms
- Animals, Brain, Cell Wall, Cloning, Molecular, Gene Expression Regulation, Gram-Negative Bacteria, Interleukin-1, Lipopolysaccharides, Male, Membrane Glycoproteins, Receptors, Cell Surface, RNA, Messenger, Sensitivity and Specificity, Rats, Sprague-Dawley, In Situ Hybridization, Lipopolysaccharide Receptors, Drosophila Proteins, Toll-Like Receptors, Toll-Like Receptor 4, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
