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Uric acid promotes an acute inflammatory response to sterile cell death in mice
Open accessAbstract
Necrosis stimulates inflammation, and this response is medically relevant because it contributes to the pathogenesis of a number of diseases. It is thought that necrosis stimulates inflammation because dying cells release proinflammatory molecules that are recognized by the immune system. However, relatively little is known about the molecular identity of these molecules and their contribution to responses in vivo. Here, we investigated the role of uric acid in the inflammatory response to necrotic cells in mice. We found that dead cells not only released intracellular stores of uric acid but also produced it in large amounts postmortem as nucleic acids were degraded. Using newly developed Tg mice that have reduced levels of uric acid either intracellularly and/or extracellularly, we found that uric acid depletion substantially reduces the cell death-induced inflammatory response. Similar results were obtained with pharmacological treatments that reduced uric acid levels either by blocking its synthesis or hydrolyzing it in the extracellular fluids. Importantly, uric acid depletion selectively inhibited the inflammatory response to dying cells but not to microbial molecules or sterile irritant particles. Collectively, our data identify uric acid as a proinflammatory molecule released from dying cells that contributes significantly to the cell death-induced inflammatory responses in vivo.
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“For example, a reduction of uric acid, which is released from dying cells and has adjuvant activity in vivo21, was associated with substantially reduced neutrophil recruitment in the liver after acetaminophen-induced injury in two different mouse models13.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [13]
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Metadata
- Authors
- Kono, H., Chen, C.-J., Ontiveros, F., & Rock, K. L.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- National Taiwan University (TW)
- Corresponding author
- Rock, Kenneth L.
- Venue
- Journal of Clinical Investigation
- Published
- 2010-06-01
- Volume
- 120
- Issue
- 6
- Pages
- 1939-1949
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2877935
- OpenAlex
- W2092946161
- Cited by
- 337
- References
- 34
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 16 · 2023: 13 · 2022: 19 · 2021: 18 · 2020: 24 · 2019: 17 · 2018: 27 · 2017: 24 · 2016: 33 · 2015: 22 · 2014: 26 · 2013: 22 · 2012: 29
- FWCI
- 18.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Funders
- Sanofi
- American Asthma Foundation
- National Institutes of Health (DK32520)
- National Institute of Allergy and Infectious Diseases (R01AI043543, R01AI078287)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 32520, P30DK032520)
- Topics
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- uric acid, sterile inflammation, necrosis, cell death, inflammation, nucleic acid degradation, proinflammatory molecules, innate immunity
- MeSH terms
- Animals, Cells, Immune System, Inflammation, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Transgenic, Necrosis, Uric Acid, Cell Death, Mice
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