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BACKGROUND AND PURPOSE: Currently there are limited medicines available for the treatment of metabolic inflammation in diseases such as obesity and type 2 diabetes (T2D). Although initially associated with B-ells, Bruton's tyrosine kinase (BTK) is present in a wide variety of cells including monocytes and macrophages, and has been implicated in the regulation of the NF-κB and NLRP3 inflammasome activity. EXPERIMENTAL APPROACH: Using in vivo models of chronic inflammation [high-fat-diet (HFD) feeding] and in vitro assays in primary murine and human macrophages we investigated if ibrutinib, an FDA approved medicine that targets BTK, may represent a novel anti-inflammatory drug for the use in treating 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. Treatment of mice fed HFD with ibrutinib inhibited the activation of BTK and reduced monocyte/macrophage recruitment to the liver, adipose tissue and kidney. Reduced inflammatory gene expression associated with decreased activation of NF-κB and the NLRP3 inflammasome in vivo. As a result, ibrutinib treated mice fed HFD had improved glycaemic control through restored signalling by the IRS-1/Akt/GSK-3β pathway; protecting mice against the development of hepatosteatosis and proteinuria. We show that inhibition of BTK reduces activation of NF-κB and the NLRP3 inflammasome specifically in primary murine and human macrophages; which are the primary target of ibrutinib in vivo in the setting of metabolic inflammation. CONCLUSIONS AND IMPLICATIONS: In the present study we provide 'proof of concept' evidence that BTK is a novel therapeutic target for the treatment of diet -metabolic inflammation. Ibrutinib may be a candidate for drug repurposing as an anti-inflammatory for the treatment of metabolic inflammation in T2D and microvascular disease.

Original publication

DOI

10.1111/bph.15182

Type

Journal article

Journal

Br J Pharmacol

Publication Date

01/07/2020