ReferenceID 3788
AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages
Ann Rheum Dis
OBJECTIVE: AMP-activated protein kinase (AMPK) is metabolic biosensor with anti-inflammatory activities. Gout is commonly associated with excesses in soluble urate and in nutrition, both of which suppress tissue AMPK act
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Record Fields
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- Reference Id
- 3788
- Evidence Id
- 20378
- Core Evidence Id
- 20378
- Source Reference Id
- 859
- Herb2 Reference Id
- HBREF001474
- Subject Paper Key
- HBIN021260_25362043
- Pubmed Id
- 25362043
- Doi
- 10.1136/annrheumdis-2014-206074
- Paper Title
- AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages
- Paper Abstract
- OBJECTIVE: AMP-activated protein kinase (AMPK) is metabolic biosensor with anti-inflammatory activities. Gout is commonly associated with excesses in soluble urate and in nutrition, both of which suppress tissue AMPK activity. Gout is driven by macrophage-mediated inflammation transduced partly by NLRP3 inflammasome activation and interleukin (IL)-1β release. Hence, we tested the hypothesis that AMPK activation limits monosodium urate (MSU) crystal-induced inflammation. METHODS: We studied bone marrow-derived macrophages (BMDMs) from AMPKα1 knockout and wild-type mice, and assessed the selective AMPK pharmacological activator A-769662 and a low concentration (10 nM) of colchicine. We examined phosphorylation (activation) of AMPKα Thr172, NLRP3 mRNA expression, and caspase-1 cleavage and IL-1β maturation using western blot and quantitative RT-PCR approaches. We also assessed subcutaneous murine air pouch inflammatory responses to MSU crystals in vivo. RESULTS: MSU crystals suppressed phosphorylation of AMPKα in BMDMs. Knockout of AMPKα1 enhanced, and, conversely, A-769662-inhibited MSU crystal-induced inflammatory responses including IL-1β and CXCL1 release in vitro and in vivo. A-769662 promoted AMPK-dependent macrophage anti-inflammatory M2 polarisation and inhibited NLRP3 gene expression, activation of caspase-1 and IL-1β. Colchicine, at low concentration (10 nM) achieved in gout flare prophylaxis dosing, promoted phosphorylation of AMPKα and macrophage M2 polarisation, and reduced activation of caspase-1 and release of IL-1β and CXCL1 by MSU crystals in BMDMs in vitro. CONCLUSIONS: AMPK activity limits MSU crystal inflammation in vitro and in vivo, and transduces multiple anti-inflammatory effects of colchicine in macrophages. Targeting increased and sustained AMPK activation in inflammatory cells merits further investigation for enhancing efficacy of prophylaxis and treatment of gouty inflammation.
- Journal
- Ann Rheum Dis
- Publish Year
- 2016
- Experiment Subject
- cells: bone marrow-derived macrophages (bmdms) from ampkα1 knockout and wild-type mice
- Experiment Type
- Cell Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages
- Bilingual Status
- semi_complete