Deletion of myeloid-PTP1B decreases MHC Class I expression and peptide presentation through an IL-10 dependent mechanism in response to LPS challenge

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Protein Tyrosine Phosphatase 1B (PTP1B) in the immune system

Journal not available online when checked 02/04/19. DOI: 10.14800/ics.965Peer reviewedPublisher PD

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE-/- mouse model of atherosclerosis with alterations in IL10/AMPKa pathway

Objective: Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD. Methods: We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed. Results: Myeloid-PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKα and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting. Conclusions: Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE−/− mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk

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Deficiency in Protein Tyrosine Phosphatase PTP1B shortens lifespan and leads to development of acute leukemia

This work was performed with the funds from the Wellcome Trust ISSF grant to M. Delibegovic and BHF project grant to M. Delibegovic (PG/11/8/28703). S. Le Sommer is a recipient of the University of Aberdeen Institute of Medical Sciences PhD studentship. Conflict of interest: Authors declare there are no conflicts of interests.Peer reviewedPostprin

Pharamcological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in LDLR-/- mouse model of atherosclerosis

The authors wish to thank Professor Nicholas Tonks for providing the PTP1B inhibitor trodusquemine; Linda Robertson for her help with the aorta histology; Dr Fiona Grieg for tuition into aortic dissection and Dr James Hislop for critical reading of this manuscript. We also wish to thank the British Heart Foundation (PG/14/43/30889) for supporting this researchPeer reviewedPublisher PD

Protein Tyrosine Phosphatase 1B in the immune system: DOI: 10.14800/ics.965

Protein Tyrosine Phosphatase 1B (PTP1B) is best known for its role in insulin and leptin signalling. Its ability to directly dephosphorylate the insulin receptor (IR) has made it a prime target for the development of anti-diabetic drugs. In recent times the role of PTP1B has been substantially expanded from a simple regulator of insulin signalling to a complex and dynamic regulator of multiple signalling pathways including the Janus kinase and signal transducer and activator of transcription (JAK-STAT) signalling, thus providing a link between metabolism and inflammation. Here, we review the inflammation associated with obesity and diabetes and the role that PTP1B may play in the development and regulation of this inflammation. We will discuss the role of PTP1B in both the innate and adaptive immune system and how the development of tissue specific knock out models have allowed us to delineate this complex system. Finally, we discuss how this new knowledge may allow us to develop safe and effective treatments for a multitude of conditions, including type 2 diabetes mellitus (T2DM), autoimmunity, and chronic inflammation

A key role for PTP1B in dendritic cell maturation, migration and T cell activation

Acknowledgements We thank the Iain Fraser Flow Cytometry Centre and the Medical Research Facility of the University of Aberdeen. We are grateful to Drs West, Zaru, and Davidson (University of Dundee) for the scientific discussion and technical assistance. Wethank Derek Mitchell (University of Dundee) for aiding with the quantification of focal contacts. Funding This work was supported by Saving Sight in Grampian and the Development Trust of the UoA (both to J.V.F.). Work on this project was partly funded by project grants from British Heart Foundation and European Foundation for the Study of Diabetes/Lilly diabetes programme grant (to M.D.).Peer reviewedPostprin