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 1

MSU crystals activate zebrafish macrophages.

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MSU crystals activate zebrafish macrophages. (A) Injection site and dors...
(A) Injection site and dorsal hindbrain view following MSU crystal injection (inset shows crystals under polarized light). (B) Expression of il1b within PBS- and MSU crystal–injected larvae. (C) Temporal quantification of il1b expression was categorized as high (B), low (Supplemental Figure 1C), or no expression (None). (D) Expression of irg1 within PBS- and MSU crystal–injected larvae. (E) Temporal quantification of irg1 expression: high (D), low (Supplemental Figure 1C), or no expression. (F) Immunofluorescence of Tnfa within the hindbrain of PBS- and MSU crystal–injected 1% DMSO–treated Tg(mpeg1:EGFP) larvae and temporal quantification in individual macrophages (G). n = 15 larvae/treatment. Arrows mark il1b/irg1 expression in the hindbrain. The numbers in parentheses in B and D indicate the frequency of larvae with the indicated phenotype.Data were pooled from 2 independent experiments and represent the mean ± SD. ****P < 0.0001, by Student’s t test. Scale bars: 50 μm (A and F), 5 μm (A, inset), and 100 μm (B). Magnification value ×6 (D).