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 7

FAO and mROS production contributes to MSU crystal–driven macrophage activation.

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FAO and mROS production contributes to MSU crystal–driven macrophage act...
(A) Expression of il1b in PBS-injected and MSU crystal–injected DMSO-, etomoxir-, and MitoTEMPO-treated larvae. The PBS and DMSO-MSU images are the same as in Figure 1B, Supplemental Figure 1G, and Supplemental Figure 7A, respectively. Arrow indicates il1b expression in the hindbrain. The numbers in parentheses indicate the frequency of larvae with the indicated phenotype. (B) Quantification of il1b expression, as detected in A. The DMSO-MSU sample is the same as in Supplemental Figure 7C. (C) Immunofluorescence of Tnfa in the hindbrains of MSU crystal–injected DMSO-, etomoxir- and MitoTEMPO-treated Tg(mpeg1:EGFP) larvae. The DMSO-MSU image is the same as in Supplemental Figure 5G. (D) Quantification of Tnfa, as detected in C (n = 15 larvae/treatment). The DMSO-MSU sample is the same as in Figure 1G (3 hpi), Figure 3D; Figure 5F; Supplemental Figure 5, D and H; and Supplemental Figure 7E. Data were pooled from 2 independent experiments and represent the mean ± SD. ****P < 0.0001, by 1-way ANOVA with Dunnett’s post hoc test. Scale bars: 100 μm (A), 50 μm (C). Eto., etomoxir; MT, MitoTEMPO.