UMMS Affiliation

Department of Pathology

Date

5-27-2010

Document Type

Article

Subjects

Animals; Cell Death; Cells; Immune System; Inflammation; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Necrosis; Uric Acid

Disciplines

Immunopathology | Life Sciences | Medicine and Health Sciences | Pathology

Abstract

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.

Rights and Permissions

Citation: J Clin Invest. 2010 Jun 1;120(6):1939-49. doi: 10.1172/JCI40124. Epub 2010 May 24. Link to article on publisher's site

DOI of Published Version

10.1172/JCI40124

Related Resources

Link to Article in PubMed

Journal Title

The Journal of clinical investigation

PubMed ID

20501947

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