| Summary: | 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.
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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.
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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.
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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.
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