OxPhos in adipose tissue macrophages regulated by BTK enhances their M2-like phenotype and confers a systemic immunometabolic benefit in obesity.

Autor:	Purvis GSD; Sir William Dunn School of Pathology, University of Oxford, UK.; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.; Division of Cardiovascular Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK., Collino M; Dept of Neurosciences 'Rita Levi Montalcini' University of Turin, Turin, IT., van Dam AD; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Einaudi G; Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy., Ng Y; Division of Cardiovascular Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.; National Institute for Health (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Shanmuganathan M; Division of Cardiovascular Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.; National Institute for Health (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Patel SY; Primary Immunodeficiency Unit, Department of Experimental Medicine, Nuffield Department of Medicine, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford, UK., Thiemermann C; The William Harvey Research Institute, Queen Mary University of London, London, UK., Channon KM; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.; Division of Cardiovascular Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.; National Institute for Health (NIHR) Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK., Greaves DR; Sir William Dunn School of Pathology, University of Oxford, UK.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2024 Jan 08. Date of Electronic Publication: 2024 Jan 08.
DOI:	10.2337/db22-0275
Abstrakt:	Bruton's tyrosine kinase (BTK) is a non-receptor bound kinase involved in pro-inflammatory signalling in activated macrophages, however, its role within adipose tissue macrophages remains unclear. We have demonstrated that BTK signalling regulates macrophage M2-like polarisation state by up-regulating subunits of mitochondrially encoded electron transport chain Complex I (ND4 and NDL4) and Complex IV (mt-CO1, mt-CO2 and mt-CO3) resulting in an enhanced rate of oxidative phosphorylation (OxPhos) in an NF-κB independent manner. Critically, BTK expression is elevated in adipose tissue macrophages from obese individuals with diabetes, while key mitochondrial genes (mtC01, mtC02 and mtC03) are decreased in inflammatory myeloid cells from obese individuals. Inhibition of BTK signalling either globally (Xid mice) or in myeloid cells (LysMCreBTK), or therapeutically (Acalabrutinib) protects HFD-fed mice from developing glycaemic dysregulation by improving signalling through the IRS1/Akt/GSK3β pathway. The beneficial effects of acalabrutinib treatment are lost in macrophage ablated mice. Inhibition of BTK signalling in myeloid cells but not B-cells, induced a phenotypic switch in adipose tissue macrophages from a pro-inflammatory M1-state to a pro-resolution M2-like phenotype, by shifting macrophage metabolism towards OxPhos. This reduces both local and systemic inflammation and protected mice from the immunometabolic consequences of obesity. Therefore, in BTK we have identified a macrophage specific, druggable target that can regulate adipose tissue polarisation and cellular metabolism that can confer systematic benefit in metabolic syndrome. (© 2024 by the American Diabetes Association.)
Databáze:	MEDLINE
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