Inhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation.
BRITISH JOURNAL OF PHARMACOLOGY(2020)
摘要
Background and Purpose There are no medications currently available to treat metabolic inflammation. Bruton's tyrosine kinase (BTK) is highly expressed in monocytes and macrophages and regulates NF-kappa B and NLRP3 inflammasome activity; both propagate metabolic inflammation in diet-induced obesity. Experimental Approach Using anin vivomodel of chronic inflammation, high-fat diet (HFD) feeding, in male C57BL/6J mice andin vitroassays in primary murine and human macrophages, we investigated if ibrutinib, an FDA approved BTK inhibitor, may represent a novel anti-inflammatory medication to treat metabolic inflammation. Key Results HFD-feeding was associated with increased BTK expression and activation, which was significantly correlated with monocyte/macrophage accumulation in the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD-fed mice inhibited the activation of BTK and reduced monocyte/macrophage recruitment to the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD-fed mice decreased the activation of NF-kappa B and the NLRP3 inflammasome. As a result, ibrutinib treated mice fed HFD had improved glycaemic control through restored signalling by the IRS-1/Akt/GSK-3 beta pathway, protecting mice against the development of hepatosteatosis and proteinuria. We show that BTK regulates NF-kappa B and the NLRP3 inflammasome specifically in primary murine and human macrophages, thein vivocellular target of ibrutinib. Conclusion and Implications We provide "proof of concept" evidence that BTK is a novel therapeutic target for the treatment of diet-induced metabolic inflammation and ibrutinib may be a candidate for drug repurposing as an anti-inflammatory agent for the treatment of metabolic inflammation in T2D and microvascular disease.
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关键词
Bruton's tyrosine kinase,diabetes,drug repurposing,macrophage,metabolic inflammation,NF-kB,NLRP3
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