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Myeloid P2Y2 receptor promotes acute inflammation but is dispensable for chronic high-fat diet-induced metabolic dysfunction

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Abstract

The purinergic receptor P2Y2 binds ATP to control chemotaxis of myeloid cells, and global P2Y2 receptor knockout mice are protected in models of acute inflammation. Chronic inflammation mediated by macrophages and other immune cells in adipose tissue contributes to the development of insulin resistance. Here, we investigate whether mice lacking P2Y2 receptors on myeloid cells are protected against acute and chronic inflammation. Wild-type mice were transplanted with either wild-type or P2Y2 receptor null bone marrow and treated with a sublethal dose of endotoxin as a model of acute inflammation, or fed a high-fat diet to induce obesity and insulin resistance as a model of chronic inflammation. P2Y2−/− chimeric mice were protected against acute inflammation. However, high-fat diet feeding induced comparable inflammation and insulin resistance in both WT and P2Y2−/− chimeric mice. Of note, confocal microscopy revealed significantly fewer crown-like structures, assemblies of macrophages around adipocytes, in P2Y2−/− chimeric mice compared to WT chimeric mice. We conclude that P2Y2 receptors on myeloid cells are important in mediating acute inflammation but are dispensable for the development of whole body insulin resistance in diet-induced obese mice.

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Funding

This study was supported by grants from the National Institutes of Health NIH-P01HL120840 (to NL). SEA was supported by an AHA predoctoral fellowship and by an NIH training grant (HL007284).

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Authors and Affiliations

  1. Department of Pharmacology, University of Virginia, PO Box 800735, Charlottesville, VA, 22908, USA

    Samantha E. Adamson, Garren Montgomery & Norbert Leitinger

  2. Cardiovascular Research Center, University of Virginia, Charlottesville, VA, 22908, USA

    Samantha E. Adamson, Scott A. Seaman, Shayn M. Peirce-Cottler & Norbert Leitinger

  3. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, 22908, USA

    Scott A. Seaman & Shayn M. Peirce-Cottler

Authors
  1. Samantha E. Adamson
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  2. Garren Montgomery
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  3. Scott A. Seaman
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  4. Shayn M. Peirce-Cottler
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  5. Norbert Leitinger
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Corresponding author

Correspondence to Norbert Leitinger.

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Conflicts of interest

Samantha E. Adamson declares that she has no conflict of interest.

Garren Montgomery declares that he has no conflict of interest.

Scott A. Seaman declares that he has no conflict of interest.

Shayn M. Peirce-Cottler declares that she has no conflict of interest.

Norbert Leitinger declares that he has no conflict of interest.

Ethical approval

All animal studies were approved by the Animal Care and Use Committee at the University of Virginia.

Electronic supplementary material

Supplementary Figure 1

P2Y2 receptor activation is not required for macrophage expression of chemokines, Cxcl1 and Cxcl2. WT and P2Y2 deficient bone marrow derived macrophages were treated with 100 μm ATP or 200 μm UTP for 6 h and mRNA of chemokines Cxcl1 and Cxcl2 was measured by qRT-PCR. Data is normalized to β2-microglobulin mRNA and expressed as mean +/− s.e.m. (A) (GIF 4 kb)

High resolution image (TIFF 114 kb)

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Adamson, S.E., Montgomery, G., Seaman, S.A. et al. Myeloid P2Y2 receptor promotes acute inflammation but is dispensable for chronic high-fat diet-induced metabolic dysfunction. Purinergic Signalling 14, 19–26 (2018). https://doi.org/10.1007/s11302-017-9589-9

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  • DOI: https://doi.org/10.1007/s11302-017-9589-9

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