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

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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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.

Original languageEnglish
Pages (from-to)1752-1771
Number of pages20
JournalJournal of Clinical Investigation
Volume128
Issue number5
DOIs
Publication statusPublished - 1 May 2018

Cite this

Hall, C. J., Sanderson, L. E., Lawrence, L. M., Pool, B., Van Der Kroef, M., Ashimbayeva, E., ... Crosier, P. S. (2018). Blocking fatty acid-fueled mROS production within macrophages alleviates acute gouty inflammation. Journal of Clinical Investigation, 128(5), 1752-1771. https://doi.org/10.1172/JCI94584
Hall, Christopher J. ; Sanderson, Leslie E. ; Lawrence, Lisa M. ; Pool, Bregina ; Van Der Kroef, Maarten ; Ashimbayeva, Elina ; Britto, Denver ; Harper, Jacquie L. ; Lieschke, Graham J. ; Astin, Jonathan W. ; Crosier, Kathryn E. ; Dalbeth, Nicola ; Crosier, Philip S. / Blocking fatty acid-fueled mROS production within macrophages alleviates acute gouty inflammation. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 5. pp. 1752-1771.
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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.",
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Hall, CJ, Sanderson, LE, Lawrence, LM, Pool, B, Van Der Kroef, M, Ashimbayeva, E, Britto, D, Harper, JL, Lieschke, GJ, Astin, JW, Crosier, KE, Dalbeth, N & Crosier, PS 2018, 'Blocking fatty acid-fueled mROS production within macrophages alleviates acute gouty inflammation', Journal of Clinical Investigation, vol. 128, no. 5, pp. 1752-1771. https://doi.org/10.1172/JCI94584

Blocking fatty acid-fueled mROS production within macrophages alleviates acute gouty inflammation. / Hall, Christopher J.; Sanderson, Leslie E.; Lawrence, Lisa M.; Pool, Bregina; Van Der Kroef, Maarten; Ashimbayeva, Elina; Britto, Denver; Harper, Jacquie L.; Lieschke, Graham J.; Astin, Jonathan W.; Crosier, Kathryn E.; Dalbeth, Nicola; Crosier, Philip S.

In: Journal of Clinical Investigation, Vol. 128, No. 5, 01.05.2018, p. 1752-1771.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Hall, Christopher J.

AU - Sanderson, Leslie E.

AU - Lawrence, Lisa M.

AU - Pool, Bregina

AU - Van Der Kroef, Maarten

AU - Ashimbayeva, Elina

AU - Britto, Denver

AU - Harper, Jacquie L.

AU - Lieschke, Graham J.

AU - Astin, Jonathan W.

AU - Crosier, Kathryn E.

AU - Dalbeth, Nicola

AU - Crosier, Philip S.

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N2 - 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.

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JF - Journal of Clinical Investigation

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Hall CJ, Sanderson LE, Lawrence LM, Pool B, Van Der Kroef M, Ashimbayeva E et al. Blocking fatty acid-fueled mROS production within macrophages alleviates acute gouty inflammation. Journal of Clinical Investigation. 2018 May 1;128(5):1752-1771. https://doi.org/10.1172/JCI94584