Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation
Christopher J. Hall, … , Nicola Dalbeth, Philip S. Crosier
Christopher J. Hall, … , Nicola Dalbeth, Philip S. Crosier
Published March 26, 2018
Citation Information: J Clin Invest. 2018;128(5):1752-1771. https://doi.org/10.1172/JCI94584.
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Research Article Immunology Inflammation

Blocking fatty acid–fueled mROS production within macrophages alleviates acute gouty inflammation

Abstract

Gout is the most common inflammatory arthritis affecting men. Acute gouty inflammation is triggered by monosodium urate (MSU) crystal deposition in and around joints that activates macrophages into a proinflammatory state, resulting in neutrophil recruitment. A complete understanding of how MSU crystals activate macrophages in vivo has been difficult because of limitations of live imaging this process in traditional animal models. By live imaging the macrophage and neutrophil response to MSU crystals within an intact host (larval zebrafish), we reveal that macrophage activation requires mitochondrial ROS (mROS) generated through fatty acid oxidation. This mitochondrial source of ROS contributes to NF-κB–driven production of IL-1β and TNF-α, which promote neutrophil recruitment. We demonstrate the therapeutic utility of this discovery by showing that this mechanism is conserved in human macrophages and, via pharmacologic blockade, that it contributes to neutrophil recruitment in a mouse model of acute gouty inflammation. To our knowledge, this study is the first to uncover an immunometabolic mechanism of macrophage activation that operates during acute gouty inflammation. Targeting this pathway holds promise in the management of gout and, potentially, other macrophage-driven diseases.

Authors

Christopher J. Hall, Leslie E. Sanderson, Lisa M. Lawrence, Bregina Pool, Maarten van der Kroef, Elina Ashimbayeva, Denver Britto, Jacquie L. Harper, Graham J. Lieschke, Jonathan W. Astin, Kathryn E. Crosier, Nicola Dalbeth, Philip S. Crosier

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Figure 13

Drugs that inhibit irg1 expression suppress MSU crystal–driven neutrophil recruitment and macrophage-specific mROS production.

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Drugs that inhibit irg1 expression suppress MSU crystal–driven neutrophi...
(A) Immunofluorescence detection of neutrophils in MSU crystal–injected DMSO-, chrysin-, piperlongumine-, and camptothecin-treated Tg(lyz:EGFP) larvae. The DMSO-MSU image is the same as in Figure 2D and Supplemental Figure 5I. (B–D) Quantification of neutrophils, as detected in A, for chrysin (B), piperlongumine (C), and camptothecin (D) treatments (n = 13–15 larvae/treatment). The DMSO-MSU samples are the same as in Figure 2, B, E, and F; Figure 4, B and C; Figure 6C; Figure 8, B and C; Figure 11, D and E; Supplemental Figure 3D; Supplemental Figure 5, F and J; Supplemental Figure 7G; and Supplemental Figure 10, B and C. (E) Macrophage mROS production (white arrow) in the hindbrains of MSU crystal–injected DMSO-, chrysin-, piperlongumine-, and camptothecin-treated Tg(mpeg1:EGFP) larvae (MitoSOX signal is displayed as a heatmap, with warmer colors representing higher levels of mROS). (F) Quantification of macrophage-specific mROS production, as detected in E (n = 10 larvae/treatment). The DMSO-MSU sample is the same as in Figure 6F; Figure 8E; Supplemental Figure 7I; and Supplemental Figure 8, B and C. Data were pooled from 2 independent experiments and represent the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Dunnett’s post hoc test. Scale bars: 50 μm (A) and 10 μm (E).