Toll-Like Receptor 4 on Nonhematopoietic Cells Sustains CNS Inflammation during Endotoxemia, Independent of Systemic Cytokines
Open accessAbstract
Inflammatory agonists such as lipopolysaccharide (LPS) induce robust systemic as well as CNS responses after peripheral administration. Responses in the innate immune system require triggering of toll-like receptor 4 (TLR4), but the origin of CNS sequelas has been controversial. We demonstrate expression of TLR4 transcripts in mouse brain in the meninges, ventricular ependyma, circumventricular organs, along the vasculature, and in parenchymal microglia. The contribution of TLR4 expressed in CNS resident versus hematopoietic cells to the development of CNS inflammation was examined using chimeric mice. Reciprocal bone marrow chimeras between wild-type and TLR4 mutant mice show that TLR4 on CNS resident cells is critically required for sustained inflammation in the brain after systemic LPS administration. Hematopoietic TLR4 alone supported the systemic release of acute phase cytokines, but transcription of proinflammatory genes in the CNS was reduced in duration. In contrast, TLR4 function in radiation-resistant cells was sufficient for inflammatory progression in the brains of chimeric mice, despite the striking absence of cytokine elevations in serum. Surprisingly, a temporal rise in serum corticosterone was also dependent on TLR4 signaling in nonhematopoietic cells. Our findings demonstrate a requirement for TLR4 function in CNS-resident cells, independent of systemic cytokine effects, for sustained CNS-specific inflammation and corticosterone rise during endotoxemia.
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Sustained brain inflammation in response to blood endotoxin requires brain TLR4, which may be on microglia, endothelium, perivascular macrophages, meninges or circumventricular organs.
“However, sustained brain inflammation in response to blood endotoxin requires brain TLR4, which may be on microglia, endothelium, perivascular macrophages, meninges or circumventricular organs [55].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [55]
The longer-term effect of blood endotoxin on the brain is not mediated by blood cytokines, but may be mediated in part by endotoxin activating brain cells to produce cytokines within the brain.
“This implies that the longer-term effect of blood endotoxin on the brain is not mediated by blood cytokines, but may be mediated in part by endotoxin activating the above cells to produce cytokines within the brain (Fig. 2).”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [55]
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- Authors
- Chakravarty, S., & Herkenham, M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Herkenham, Miles
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-02-16
- Volume
- 25
- Issue
- 7
- Pages
- 1788-1796
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725921
- OpenAlex
- W2010801051
- Cited by
- 396
- References
- 30
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 12 · 2023: 10 · 2022: 18 · 2021: 14 · 2020: 16 · 2019: 12 · 2018: 21 · 2017: 15 · 2016: 15 · 2015: 20 · 2014: 32 · 2013: 30 · 2012: 31
- FWCI
- 13.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health
- 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
- TLR4, neuroinflammation, endotoxemia, lipopolysaccharide, non-hematopoietic cells, microglia, chimeric mice, bone marrow chimeras, circumventricular organs, meninges, ependyma, corticosterone, systemic cytokines, innate immunity
- MeSH terms
- NF-KappaB Inhibitor alpha, CX3C Chemokine Receptor 1, Animals, Brain, Choroid Plexus, Corticosterone, Encephalitis, Gene Expression Regulation, Hypothalamo-Hypophyseal System, Lipopolysaccharides, Male, Meninges, Mice, Inbred C3H, Mice, Inbred C57BL, Pituitary-Adrenal System, Radiation Chimera, Receptors, Immunologic, RNA, Messenger, Spleen, Bone Marrow Transplantation, Cytokines, Cell Lineage, Endotoxemia, Receptors, Chemokine, I-kappa B Proteins, Toll-Like Receptor 4, Mice
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