Inhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation
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 mon...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2020
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| _version_ | 1797103155017678848 |
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| author | Purvis, GSD Collino, M Aranda-Tavio, H Chiazza, F O'Riordan, CE Zeboudj, L Mohammad, S Collotta, D Verta, R Guisot, NES Bunyard, P Yaqoob, MM Greaves, DR Thiemermann, C |
| author_facet | Purvis, GSD Collino, M Aranda-Tavio, H Chiazza, F O'Riordan, CE Zeboudj, L Mohammad, S Collotta, D Verta, R Guisot, NES Bunyard, P Yaqoob, MM Greaves, DR Thiemermann, C |
| author_sort | Purvis, GSD |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T06:16:04Z |
| format | Journal article |
| id | oxford-uuid:f11d90b0-752c-4153-82e3-3c99e505acff |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:16:04Z |
| publishDate | 2020 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:f11d90b0-752c-4153-82e3-3c99e505acff2022-03-27T11:53:37ZInhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f11d90b0-752c-4153-82e3-3c99e505acffEnglishSymplectic ElementsWiley 2020Purvis, GSDCollino, MAranda-Tavio, HChiazza, FO'Riordan, CEZeboudj, LMohammad, SCollotta, DVerta, RGuisot, NESBunyard, PYaqoob, MMGreaves, DRThiemermann, CBackground 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. <br></br> 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. <br></br> 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. <br></br> 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. |
| spellingShingle | Purvis, GSD Collino, M Aranda-Tavio, H Chiazza, F O'Riordan, CE Zeboudj, L Mohammad, S Collotta, D Verta, R Guisot, NES Bunyard, P Yaqoob, MM Greaves, DR Thiemermann, C Inhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation |
| title | Inhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation |
| title_full | Inhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation |
| title_fullStr | Inhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation |
| title_full_unstemmed | Inhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation |
| title_short | Inhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation |
| title_sort | inhibition of bruton s tyrosine kinase regulates macrophage nf κb and nlrp3 inflammasome activation in metabolic inflammation |
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