CoChat
Sign Up
Cited by 1,052Neuroinflammation and Neurodegeneration MechanismsImmune Response and InflammationInflammasome and immune disorders

Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway

Open access
Lehnardt, Seija, Massillon, Leon, Follett, Pamela, Jensen, Frances E., Ratan, Rajiv, Rosenberg, Paul A., Volpe, Joseph J., Vartanian, Timothy·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1432609100PMC PMC166260
Open this paper in CoChat — free account

Abstract

Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from tlr4 mutant mice. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the tlr4 gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.1432609100

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Activation of microglia with LPS and injection of LPS in the brain induce IL-1β and NO production via Nox1.

    “activation of microglia with lipopolysaccharide (LPS), a component of Gram-negative bacteria commonly used to model proinflammatory and neurotoxic activation of microglia (Lehnardt et al., 2003;Qin et al., 2004), and injection of LPS in the brain induce IL-1␤ and NO⅐ production via Nox1”

    From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Lehnardt et al., 2003

  • LPS signals through TLR4, which promotes LPS-triggered microglial neurotoxicity.

    “LPS signals through the toll-like receptor 4 (TLR4), which promotes LPS-triggered microglial neurotoxicity (Lehnardt et al., 2003)”

    From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Lehnardt et al., 2003

  • TLR4 is a unique pattern recognition receptor, and TLR4 in the brain is mainly expressed in microglia.

    “As we know, toll-like receptor 4 (TLR4) is a unique pattern recognition receptor (PRR), and TLR4 in the brain is mainly expressed in microglia (Seija Lehnardt et al. 2003).”

    From Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer’s disease and Parkinson’s disease (2020) · cites this paper as Seija Lehnardt et al. 2003

  • TLR4 expression is significantly elevated in brain tissue of AD and PD patients and mice, and the aggregation of α-syn and Aβ is related to the activation of TLR4.

    “Studies also indicate that TLR4 expression is significantly elevated in brain tissue of AD and PD patients and mice, and the aggregation of α-syn and Aβ is related to the activation of TLR4 (Seija Lehnardt et al. 2003).”

    From Therapeutic effect of GLP-1 engineered strain on mice model of Alzheimer’s disease and Parkinson’s disease (2020) · cites this paper as Seija Lehnardt et al. 2003

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 41

  1. [1]Kreutzberg, G. W. (1996) Trends Neurosci. 19 312-318. [DOI] [PubMed] [Google Scholar]
  2. [2]Dickson, D. W., Lee, S. C., Mattiace, L. A., Yen, S. H. & Brosnan, C. (1993) Glia 7 75-83. [DOI] [PubMed] [Google Scholar]
  3. [3]McGeer, P. L., Itagaki, S., Boyes, B. E. & McGeer, E. G. (1988) Neurology 38 1285-1291. [DOI] [PubMed] [Google Scholar]
  4. [4]Trapp, B. D., Bo, L., Mork, S. & Chang, A. (1999) J. Neuroimmunol. 98 49-56. [DOI] [PubMed] [Google Scholar]
  5. [5]Giulian, D., Wendt, E., Vaca, K. & Noonan, C. A. (1993) Proc. Natl. Acad. Sci. USA 90 2769-2773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. [6]McDonald, D. R., Brunden, K. R. & Landreth, G. E. (1997) J. Neurosci. 17 2284-2294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. [7]Liberatore, G. T., Jackson-Lewis, V., Vukosavic, S., Mandir, A. S., Vila, M., McAuliffe, W. G., Dawson, V. L., Dawson, T. M. & Przedborski, S. (1999) Nat. Med. 5 1403-1409. [DOI] [PubMed] [Google Scholar]
  8. [8]Medzhitov, R. & Janeway, C. A., Jr. (1997) Curr. Opin. Immunol. 9 4-9. [DOI] [PubMed] [Google Scholar]
  9. [9]Medzhitov, R. & Janeway, C., Jr. (2000) Immunol. Rev. 173 89-97. [DOI] [PubMed] [Google Scholar]
  10. [10]Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K. & Akira, S. (1999) J. Immunol. 162 3749-3752. [PubMed] [Google Scholar]
  11. [11]Wright, S. D. (1999) J. Exp. Med. 189 605-609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. [12]Medzhitov, R., Preston-Hurlburt, P., Kopp, E., Stadlen, A., Chen, C., Ghosh, S. & Janeway, C. A., Jr. (1998) Mol. Cell 2 253-258. [DOI] [PubMed] [Google Scholar]
  13. [13]Shimazu, R., Akashi, S., Ogata, H., Nagai, Y., Fukudome, K., Miyake, K. & Kimoto, M. (1999) J. Exp. Med. 189 1777-1782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. [14]Lacroix, S., Feinstein, D. & Rivest, S. (1998) Brain Pathol. 8 625-640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. [15]Laflamme, N. & Rivest, S. (2001) FASEB J. 15 155-163. [DOI] [PubMed] [Google Scholar]
  16. [16]Lehnardt, S., Lachance, C., Patrizi, S., Lefebvre, S., Follett, P. L., Jensen, F. E., Rosenberg, P. A., Volpe, J. J. & Vartanian, T. (2002) J. Neurosci. 22 2478-2486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. [17]Murphy, T. H., Schnaar, R. L. & Coyle, J. T. (1990) FASEB J. 4 1624-1633. [PubMed] [Google Scholar]
  18. [18]Vartanian, T., Li, Y., Zhao, M. & Stefansson, K. (1995) Mol. Med. 1 732-743. [PMC free article] [PubMed] [Google Scholar]
  19. [19]Eklind, S., Mallard, C., Leverin, A. L., Gilland, E., Blomgren, K., Mattsby-Baltzer, I. & Hagberg, H. (2001) Eur. J. Neurosci. 13 1101-1106. [DOI] [PubMed] [Google Scholar]
  20. [20]Chang, R. C., Hudson, P. M., Wilson, B. C., Liu, B., Abel, H. & Hong, J. S. (2000) Neuroscience 97 757-764. [DOI] [PubMed] [Google Scholar]
  21. [21]Jeohn, G. H., Kim, W. G. & Hong, J. S. (2000) Brain Res. 880 173-177. [DOI] [PubMed] [Google Scholar]
  22. [22]Becher, B., Fedorowicz, V. & Antel, J. P. (1996) J. Neurosci. Res. 45 375-381. [DOI] [PubMed] [Google Scholar]
  23. [23]Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Huffel, C. V., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998) Science 282 2085-2088. [DOI] [PubMed] [Google Scholar]
  24. [24]Qureshi, S. T., Lariviere, L., Leveque, G., Clermont, S., Moore, K. J., Gros, P. & Malo, D. (1999) J. Exp. Med. 189 615-625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. [25]Chao, C. C., Hu, S., Molitor, T. W., Shaskan, E. G. & Peterson, P. K. (1992) J. Immunol. 149 2736-2741. [PubMed] [Google Scholar]
  26. [26]Lee, S. C., Liu, W., Dickson, D. W., Brosnan, C. F. & Berman, J. W. (1993) J. Immunol. 150 2659-2667. [PubMed] [Google Scholar]
  27. [27]Wu, D. C., Jackson-Lewis, V., Vila, M., Tieu, K., Teismann, P., Vadseth, C., Choi, D. K., Ischiropoulos, H. & Przedborski, S. (2002) J. Neurosci. 22 1763-1771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. [28]Ullrich, O., Diestel, A., Eyupoglu, I. Y. & Nitsch, R. (2001) Nat. Cell Biol. 3 1035-1042. [DOI] [PubMed] [Google Scholar]
  29. [29]Meda, L., Cassatella, M. A., Szendrei, G. I., Otvos, L., Jr., Baron, P., Villalba, M., Ferrari, D. & Rossi, F. (1995) Nature 374 647-650. [DOI] [PubMed] [Google Scholar]
  30. [30]Gonzalez-Scarano, F. & Baltuch, G. (1999) Annu. Rev. Neurosci. 22 219-240. [DOI] [PubMed] [Google Scholar]
  31. [31]Rinner, W. A., Bauer, J., Schmidts, M., Lassmann, H. & Hickey, W. F. (1995) Glia 14 257-266. [DOI] [PubMed] [Google Scholar]
  32. [32]Richardson, A., Hao, C. & Fedoroff, S. (1993) Glia 7 25-33. [DOI] [PubMed] [Google Scholar]
  33. [33]Hickey, W. F., Vass, K. & Lassmann, H. (1992) J. Neuropathol. Exp. Neurol. 51 246-256. [DOI] [PubMed] [Google Scholar]
  34. [34]Leon, S., Yin, Y., Nguyen, J., Irwin, N. & Benowitz, L. I. (2000) J. Neurosci. 20 4615-4626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. [35]Wyss-Coray, T., Lin, C., Yan, F., Yu, G. Q., Rohde, M., McConlogue, L., Masliah, E. & Mucke, L. (2001) Nat. Med. 7 612-618. [DOI] [PubMed] [Google Scholar]
  36. [36]Prewitt, C. M., Niesman, I. R., Kane, C. J. & Houle, J. D. (1997) Exp. Neurol. 148 433-443. [DOI] [PubMed] [Google Scholar]
  37. [37]Coyle, J. T. & Puttfarcken, P. (1993) Science 262 689-695. [DOI] [PubMed] [Google Scholar]
  38. [38]Beal, M. F. (1995) Ann. Neurol. 38 357-366. [DOI] [PubMed] [Google Scholar]
  39. [39]Lee, J. M., Grabb, M. C., Zipfel, G. J. & Choi, D. W. (2000) J. Clin. Invest. 106 723-731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. [40]Beal, M. F. (1992) Ann. Neurol. 31 119-130. [DOI] [PubMed] [Google Scholar]
  41. [41]Lee, J. M., Zipfel, G. J. & Choi, D. W. (1999) Nature 399 A7-A14. [DOI] [PubMed] [Google Scholar]

Cited by

Sorted by citations

Related

Authors
Lehnardt, S., Massillon, L., Follett, P., Jensen, F. E., Ratan, R., Rosenberg, P. A., Volpe, J. J., & Vartanian, T.
Affiliations
Beth Israel Deaconess Medical Center (US)
Corresponding author
Vartanian, Timothy
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-06-24
Volume
100
Issue
14
Pages
8514-8519
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1432609100
PMC
PMC166260
OpenAlex
W2109342780
Cited by
1,052
References
42
Citations by year
2026: 17 · 2025: 26 · 2024: 34 · 2023: 28 · 2022: 36 · 2021: 71 · 2020: 52 · 2019: 30 · 2018: 59 · 2017: 50 · 2016: 47 · 2015: 51 · 2014: 64 · 2013: 70 · 2012: 57
FWCI
20.56
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Public Health Service (K02N502028)
  • National Institute of Neurological Disorders and Stroke (P01 NS 38475, P01NS038475)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655, P30HD-18655)
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
innate immunity, neurodegeneration, TLR4, microglia, lipopolysaccharide, neuronal cell death, hypoxia-ischemia, axonal loss, pathogen-associated molecular patterns, central nervous system
MeSH terms
Animals, Cerebral Cortex, Chick Embryo, Ganglia, Spinal, Immunity, Innate, Lipopolysaccharides, Mice, Inbred BALB C, Mice, Inbred C3H, Nerve Degeneration, Neurons, Spinal Cord, Rats, Sprague-Dawley, Apoptosis, Microglia, Coculture Techniques, Lipopolysaccharide Receptors, Hypoxia-Ischemia, Brain, Bystander Effect, Mice, 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