CD 14 is a key organizer of microglial responses to CNS infection and injury
Abstract
Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon β-mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.
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RNA-seq data from postnatal primary microglia cell culture experiments showed that Tet2 expression was increased both at low and high levels of LPS treatment, as well as after treatment with fibronectin.
“We further validated our observations by analyzing RNA sequencing (RNA-seq) data from postnatal primary microglia cell culture experiments (Janova et al., 2016), which showed that Tet2 expression was increased both at low and high levels of LPS treatment, as well as after treatment with fibronectin, which also promotes inflammation (Figure S1A).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Janova et al., 2016
The expression pattern in BV2 cells after LPS treatment is very similar to previously published RNA-seq data from LPS-treated primary microglia cells.
“We first confirmed that the expression pattern in our BV2 cells after LPS treatment is very similar to previously published RNA-seq data from LPS-treated primary microglia cells in (Janova et al., 2016) (Figure S3A).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Janova et al., 2016
Tet2 expression is induced under inflammatory conditions mediated by different TLR agonists and fibronectin.
“We and others (Janova et al., 2016), have observed that Tet2 expression is induced under inflammatory conditions mediated by different TLR agonists and fibronectin (Figure S1A-C).”
From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Janova et al., 2016
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References 38 · Cited by 105
- Authors
- Janova, H., Böttcher, C., Holtman, I. R., Regen, T., van Rossum, D., Götz, A., Ernst, A., Fritsche, C., Gertig, U., Saiepour, N., Gronke, K., Wrzos, C., Ribes, S., Rolfes, S., Weinstein, J., Ehrenreich, H., Pukrop, T., Kopatz, J., Stadelmann, C., Salinas‐Riester, G., Weber, M. S., Prinz, M., Brück, W., Eggen, B. J. L., Boddeke, H. W. G. M., Priller, J., & Hanisch, U.
- Affiliations
- Institute of Neuropathology, University of Göttingen Göttingen 37075 Germany
- Charité – Universitätsmedizin Berlin (DE)
- University Medical Center Groningen (NL)
- Johannes Gutenberg University Mainz (DE)
- University of Göttingen (DE)
- University of Washington (US)
- Max Planck Institute of Experimental Medicine (DE)
- Universitätsmedizin Göttingen (DE)
- University of Bonn (DE)
- Transcriptome Analysis Laboratory University of Göttingen Göttingen 37077 Germany
- University of Freiburg (DE)
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2015-12-18
- Volume
- 64
- Issue
- 4
- Pages
- 635-649
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- OpenAlex
- W2210133089
- Cited by
- 105
- References
- 38
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 16 · 2023: 9 · 2022: 24 · 2021: 7 · 2020: 9 · 2019: 9 · 2018: 4 · 2017: 13 · 2016: 3
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS076620, K02NS065008)
- 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
- CD14, microglia, TLR4, lipopolysaccharide, central nervous system infection, central nervous system injury, traumatic brain injury, ischemic stroke, interferon-beta, inflammatory cytokines, damage-associated molecular patterns, neuroinflammation, innate immunity, immune cell recruitment
- MeSH terms
- Animals, Brain, Brain Injuries, Cells, Cultured, Brain Ischemia, Disease Models, Animal, Escherichia coli, Escherichia coli Infections, Lipopolysaccharides, Macrophages, Male, Mice, Inbred C57BL, Neuroimmunomodulation, Interferon-beta, Microglia, Mice, Knockout, Lipopolysaccharide Receptors, Infarction, Middle Cerebral Artery, Stroke, Feedback, Physiological, Adaptor Proteins, Vesicular Transport, Toll-Like Receptor 4
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