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 6

Irg1 contributes to MSU crystal–driven neutrophil recruitment and macrophage-specific mROS production.

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Irg1 contributes to MSU crystal–driven neutrophil recruitment and macrop...
(A) Immunofluorescence detection of neutrophils in the hindbrains of control MO–, Irg1 SBMO1–, Irg1 gRNA–, and Cas9 plus Irg1 gRNA–injected Tg(lyz:EGFP) larvae following MSU crystal injection. The control MO-MSU image is the same as in Supplemental Figure 3, B and G, and Supplemental Figure 4H. (B and C) Temporal quantification of neutrophils in the hindbrain, as detected in A, for Irg1 SBMO1–injected (B) and CRISPR-Cas9 F0 irg1 mutants (C). n = 13–15 larvae/treatment. The control MO-MSU samples in B are the same as in Supplemental Figure 3, C, H, I, and Supplemental Figure 4I. The DMSO-MSU samples in C are the same as in Figure 2, B, E, and F; Figure 4, B and C; Supplemental Figure 3D; and Supplemental Figure 5, F and J. (D) Macrophage mROS production (white arrows) in the hindbrains of control MO–, Irg1 SBMO1–, Irg1 gRNA–, and Cas9 plus Irg1 gRNA–injected Tg(mpeg1:EGFP) larvae following MSU crystal injection (MitoSOX signal is displayed as a heatmap, with warmer colors representing higher levels of mROS). (E and F) Quantification of macrophage-specific mROS production, as detected in D, for Irg1 SBMO1-injected (E) and CRISPR-Cas9 F0 irg1 mutants (F). n = 10 larvae/treatment. Data were pooled from 2 independent experiments and represent the mean ± SD. ***P < 0.001 and ****P < 0.0001, by 1-way ANOVA, Dunnett’s post hoc test. Scale bars: 50 μm (A) and 10 μm (D).