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Uric acid promotes an acute inflammatory response to sterile cell death in mice
Hajime Kono, … , Fernando Ontiveros, Kenneth L. Rock
Hajime Kono, … , Fernando Ontiveros, Kenneth L. Rock
Published May 24, 2010
Citation Information: J Clin Invest. 2010;120(6):1939-1949. https://doi.org/10.1172/JCI40124.
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Research Article

Uric acid promotes an acute inflammatory response to sterile cell death in mice

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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.

Authors

Hajime Kono, Chun-Jen Chen, Fernando Ontiveros, Kenneth L. Rock

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Figure 1

Generation and characterization of uricase Tg mice.

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Generation and characterization of uricase Tg mice.
(A) Construct of uri...
(A) Construct of uricase transgenes. Secreted uricase (ssUOX) was generated by N-terminal addition of a signal sequence for secretion derived from adenovirus gp19K (gp19K-ss). The unmodified intracellular uricase (intUOX) has a C-terminal peroxisome targeting signal sequence (PTS). (B) Western blot of uricase and α-tubulin (loading control) in organs of Tg or WT mice. (C) Uricase activity in organs and serum. WT C57BL/6 mice were injected with 9 μg of i.p. and 9 μg of i.v. rasburicase where indicated. Organs were harvested from untreated WT, uricase Tg mice, or WT mice 18 hours after rasburicase injection, and lysates were prepared. Twenty μl of lysate form various organs was added to 1 ml of uric acid solution (OD292 = 1.0) and incubated at 37°C for indicated periods of time. The uricase activity was measured by the decrease of OD292. (D) Amount of uric acid in peritoneal cavity in WT and uricase Tg mice (n = 6). (E) Plasma concentration of uric acid in WT and uricase Tg mice. Samples were drawn and immediately chilled on ice to prevent uricase from oxidizing uric acid ex vivo (n = 13–19). (F) Total neutrophil numbers in the peritoneal cavity after 15 hours after i.p. injection of 2 mg of monosodium urate crystal. n = 6 (PBS); n = 15 (WT); n = 8 (ssUOX). **P < 0.01; *P < 0.05 versus WT in (D–F).

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