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 11

Exogenous H2O2 can rescue MSU crystal–driven macrophage-specific Tnfa production and neutrophil recruitment following endogenous mROS depletion.

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Exogenous H2O2 can rescue MSU crystal–driven macrophage-specific Tnfa pr...
(A) Immunofluorescence of Tnfa in the hindbrains of MSU crystal–injected Tg(mpeg1:EGFP) larvae treated with DMSO, STAT3 IP (125 μM), MitoTEMPO (250 μM) (with and without coinjection of 50 μM H2O2), or dnikbaa with MitoTEMPO (250 μM) plus 50 μM H2O2. The DMSO-MSU image is the same as in Figure 3C, Supplemental Figure 5C, and Supplemental Figure 7D. (B) Quantification of Tnfa, as detected in A (n = 15 larvae/treatment). The DMSO-MSU sample is the same as in Figure 1G (3 hpi); Figure 3D; Figure 5F; Figure 7D; Supplemental Figure 5, D and H; and Supplemental Figure 7E. (C) Immunofluorescence detection of neutrophils in the hindbrains of MSU crystal–injected Tg(lyz:EGFP) larvae treated with DMSO, SAT3 IP (125 μM), MitoTEMPO (250 μM) (with and without coinjected 50 μM H2O2), or dnikbaa with MitoTEMPO (250 μM) plus 50 μM H2O2. The DMSO-MSU image is the same as in Figure 4A; Supplemental Figure 3B; and Supplemental Figure 5E. (D and E) Quantification of neutrophils, as detected in C, for STAT3 IP and H2O2 treatments (D) and MitoTEMPO, H2O2, and dnikbaa treatments (E) (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; Supplemental Figure 3D; Supplemental Figure 5, F and J; Supplemental Figure 7G. Data were pooled from 2 independent experiments. Data 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 C).