|Title:||Inhibition of Bruton's TK regulates macrophage NF‐κB and NLRP3 inflammasome activation in metabolic inflammation||Authors:||Purvis, Gareth S.D.
Aranda Tavío, Haidee Magdalena
O'Riordan, Caroline E.
Guisot, Nicolas E.S.
Yaqoob, Magdi M.
Greaves, David R.
|UNESCO Clasification:||32 Ciencias médicas
|Keywords:||Bruton's tyrosine kinase
Drug repurposing, et al
|Issue Date:||2020||Journal:||British journal of pharmacology||Abstract:||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-κB and NLRP3 inflammasome activity; both propagate metabolic inflammation in diet-induced obesity. Experimental approach: Using an in vivo model of chronic inflammation, high-fat diet (HFD) feeding, in male C57BL/6J mice and in vitro assays 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-κB 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-3β pathway, protecting mice against the development of hepatosteatosis and proteinuria. We show that BTK regulates NF-κB and the NLRP3 inflammasome specifically in primary murine and human macrophages, the in vivo cellular 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.||URI:||http://hdl.handle.net/10553/77864||ISSN:||0007-1188||DOI:||10.1111/bph.15182||Source:||British journal of pharmacology [0007-1188], n. 19, p. 4416-4432|
|Appears in Collections:||Artículos|
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