NLRP3-Inflammasome Activating DAMPs Stimulate an Inflammatory Response in Glia in the Absence of Priming Which Contributes to Brain Inflammation after Injury
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Inflammation in the absence of infection (sterile inflammation) contributes to acute injury and chronic disease. Cerebral ischemia is a devastating condition in which the primary injury is caused by reduced blood supply and is therefore sterile. The cytokine interleukin-1β (IL-1β) is a key contributor to ischemic brain injury and central inflammatory responses. The release of IL-1β is regulated by the protease caspase-1, and its activating complex, the inflammasome. Of the known inflammasomes the best characterized, and one that is perceived to sense sterile injury is formed by a pattern recognition receptor called NOD-like receptor pyrin domain containing three (NLRP3). A key feature of NLRP3-inflammasome dependent responses in vitro in macrophages is the requirement of an initial priming stimulus by a pathogen (PAMP), or damage associated molecular pattern (DAMP) respectively. We sought to determine the inflammatory responses of NLRP3-activating DAMPs on brain derived mixed glial cells in the absence of an initial priming stimulus in vitro. In cultured mouse mixed glia the DAMPs ATP, monosodium urate, and calcium pyrophosphate dehydrate crystals had no effect on the expression of IL-1α or IL-1β and induced release only when the cells were primed with a PAMP. In the absence of priming, these DAMPs did however induce inflammation via the production of IL-6 and CXCL1, and the release of the lysosomal protease cathepsin B. Furthermore, the acute phase protein serum amyloid A (SAA) acted as a priming stimulus on glial cells resulting in levels of IL-1 expression comparable to those induced by the PAMP lipopolysaccharide. In vivo, after cerebral ischemia, IL-1 production contributed to increased IL-6 and CXCL1 since these cytokines were profoundly reduced in the ischemic hemispheres from IL-1α/β double KO mice, although injury-induced cytokine responses were not abolished. Thus, DAMPs augment brain inflammation by directly stimulating production of glial derived inflammatory mediators. This is markedly enhanced by DAMP-induced IL-1-release-dependent responses that require a sterile endogenous priming stimulus such as SAA.
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DAMP stimulation of PRRs on microglia, such as CR3 and TLR4, mediates activation of pro-inflammatory signalling transducers NLRP3 inflammasome, NFκB and MAPKs, such as ERK.
“DAMP stimulation of PRRs on microglia, such as CR3 and toll-like receptor 4 (TLR4), mediates activation of pro-inflammatory signalling transducers NLRP3 inflammasome, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and mitogen-activated protein kinases (MAPKs), such as ERK [86,91,92].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [91]
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- Authors
- Savage, C. D., Lopez-Castejon, G., Denes, A., & Brough, D.
- Affiliations
- University of Manchester (GB)
- Corresponding author
- Brough, David
- ORCID
- Brough, David
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2012
- Volume
- 3
- Pages
- 288-288
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC3444764
- OpenAlex
- W2137425777
- Cited by
- 197
- References
- 47
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 13 · 2023: 14 · 2022: 10 · 2021: 16 · 2020: 16 · 2019: 20 · 2018: 10 · 2017: 19 · 2016: 24 · 2015: 11 · 2014: 16 · 2013: 13
- FWCI
- 5.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (201024)
- European Commission (202213, 201024)
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- NLRP3 inflammasome, damage-associated molecular patterns, sterile inflammation, cerebral ischemia, glial cells, IL-1β, interleukin-1 alpha, serum amyloid A, cathepsin B, interleukin-6, CXCL1, ATP, monosodium urate, lipopolysaccharide, neuroinflammation
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