Inhibition of Bruton's TK regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation.
Bruton's tyrosine kinase
NF-kB
NLRP3
diabetes
drug repurposing
macrophage
metabolic inflammation
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
21
01
2020
revised:
11
06
2020
accepted:
14
06
2020
pubmed:
2
7
2020
medline:
22
6
2021
entrez:
2
7
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32608058
doi: 10.1111/bph.15182
pmc: PMC7484557
doi:
Substances chimiques
Inflammasomes
0
NF-kappa B
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Nlrp3 protein, mouse
0
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4416-4432Subventions
Organisme : British Heart Foundation
ID : RG/15/10/23915
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/15/10/31485
Pays : United Kingdom
Organisme : Bart's and The London Charity Centre of Diabetic Kidney Disease
Organisme : Queen Mary University of London to C.E.O. William Harvey Research Foundation
Organisme : Oxford BHF Centre of Research Excellence
ID : RE/13/1/30181
Organisme : British Heart Foundation
ID : FS/13/58/30648
Pays : United Kingdom
Informations de copyright
© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
Br J Pharmacol. 2019 Dec;176 Suppl 1:S1-S20
pubmed: 31710719
FEBS Lett. 2008 Jan 9;582(1):97-105
pubmed: 18053812
Br J Pharmacol. 2018 Apr;175(7):987-993
pubmed: 29520785
Front Endocrinol (Lausanne). 2013 Jan 08;3:181
pubmed: 23316186
J Immunol. 2018 Apr 1;200(7):2352-2361
pubmed: 29483358
Front Immunol. 2018 Jun 20;9:1419
pubmed: 29973940
Leuk Lymphoma. 2012 Dec;53(12):2362-70
pubmed: 22616724
J Clin Invest. 2004 Feb;113(3):474-81
pubmed: 14755344
Nat Commun. 2015 Jun 10;6:7360
pubmed: 26059659
Br J Pharmacol. 2018 Feb;175(3):407-411
pubmed: 29350411
Diabetes. 2015 Oct;64(10):3355-62
pubmed: 26038580
Nat Med. 2005 Feb;11(2):191-8
pubmed: 15685170
Biol Res. 2018 Mar 31;51(1):9
pubmed: 29604956
Nutr Metab Cardiovasc Dis. 2004 Oct;14(5):228-32
pubmed: 15673055
Am J Physiol Renal Physiol. 2011 Dec;301(6):F1358-66
pubmed: 21880831
J Clin Invest. 2017 Jan 3;127(1):1-4
pubmed: 28045402
Science. 2015 Jan 23;347(6220):1260419
pubmed: 25613900
Diabetologia. 2018 Feb;61(2):482-495
pubmed: 29085990
Nat Rev Genet. 2008 Nov;9(11):819-30
pubmed: 18852695
Br J Pharmacol. 2020 Oct;177(19):4416-4432
pubmed: 32608058
Br J Pharmacol. 2019 Dec;176 Suppl 1:S247-S296
pubmed: 31710716
Br J Pharmacol. 2019 Dec;176 Suppl 1:S397-S493
pubmed: 31710713
Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13075-80
pubmed: 20615965
Br J Pharmacol. 2019 Dec;176 Suppl 1:S297-S396
pubmed: 31710714
Mol Med. 2016 Mar;21(1):1025-1037
pubmed: 26623925
Br J Pharmacol. 2010 Aug;160(7):1577-9
pubmed: 20649561
Diabetes. 2015 Jun;64(6):2015-27
pubmed: 25626735
Nat Med. 2011 Feb;17(2):179-88
pubmed: 21217695
Front Immunol. 2019 Sep 06;10:2129
pubmed: 31552054
Am J Kidney Dis. 2014 Feb;63(2 Suppl 2):S39-62
pubmed: 24461729
PLoS One. 2014 Jan 21;9(1):e85834
pubmed: 24465735
Arthritis Res Ther. 2018 Jan 25;20(1):10
pubmed: 29370834
Front Immunol. 2019 Mar 27;10:571
pubmed: 30972066
Science. 1993 Jul 16;261(5119):358-61
pubmed: 8332901
Blood. 2007 Mar 15;109(6):2521-8
pubmed: 17105816
J Am Soc Nephrol. 2016 Sep;27(9):2564-75
pubmed: 27516236
EMBO Rep. 2003 Jan;4(1):31-6
pubmed: 12524517
Lancet. 2011 Aug 27;378(9793):804-14
pubmed: 21872749
Kidney Int. 2011 Jul;80(1):68-78
pubmed: 21508925
Cell Metab. 2010 Jan;11(1):84-92
pubmed: 20074531