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

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posted on 2024-01-08, 20:36 authored by Gareth S. D. Purvis, Massimo Collino, Andrea D. van Dam, Giacomo Einaudi, Yujung Ng, Mayooran Shanmuganathan, Smita Y. Patel, Christoph Thiemermann, Keith M. Channon, David R. Greaves

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-kB 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/GSK3b 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.

Funding

This work was funded by the British Heart Foundation Grant Number: RG/15/10/23915 to DRG and RG/15/10/31485, RG/17/10/32859 and CH/16/1/32013 to KMC. National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (RG/13/1/301810) to OXAMI Study. MS was supported by the Alison Brading Memorial Scholarship in Medical Sciences, Lady Margret Hall, University of Oxford. Pump Prime award from the Oxford British Heart Foundation Research Excellence: Grant Number: RE/13/1/30181 to GSDP and DRG. Novo Nordisk-Oxford Postdoctoral Fellowship to ADvD. The transcriptomic analysis was supported by the Wellcome Trust Core Award Grant Number 203141/Z/16/Z with additional support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference (203141/Z/16/Z) for the generation and initial processing of the sequencing data.

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