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The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

Author

Listed:
  • Mahbubur Rahman

    (Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck)

  • Sajjad Muhammad

    (Institute of Pharmacology, University of Heidelberg
    Present address: Department of Neurosurgery, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany)

  • Mahtab A. Khan

    (Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck)

  • Hui Chen

    (Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck)

  • Dirk A. Ridder

    (Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck)

  • Helge Müller-Fielitz

    (Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck)

  • Barbora Pokorná

    (Institute of Pharmacology, University of Heidelberg)

  • Tillman Vollbrandt

    (Institute for Systemic Inflammation Research, University of Lübeck)

  • Ines Stölting

    (Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck)

  • Roger Nadrowitz

    (Institute of Radiotherapy and Nuclear Medicine, University of Lübeck)

  • Jürgen G Okun

    (University Hospital)

  • Stefan Offermanns

    (Max-Planck-Institute for Heart and Lung Research
    Medical Faculty, Goethe University)

  • Markus Schwaninger

    (Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck
    DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel)

Abstract

The ketone body β-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA2, GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2−/− mice. We further demonstrate that nicotinic acid, a clinically used HCA2 agonist, reduces infarct size via a HCA2-mediated mechanism, and that noninflammatory Ly-6CLo monocytes and/or macrophages infiltrating the ischemic brain also express HCA2. Using cell ablation and chimeric mice, we demonstrate that HCA2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD2 production by COX1 and the haematopoietic PGD2 synthase. Our data suggest that HCA2 activation by dietary or pharmacological means instructs Ly-6CLo monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

Suggested Citation

  • Mahbubur Rahman & Sajjad Muhammad & Mahtab A. Khan & Hui Chen & Dirk A. Ridder & Helge Müller-Fielitz & Barbora Pokorná & Tillman Vollbrandt & Ines Stölting & Roger Nadrowitz & Jürgen G Okun & Stefan , 2014. "The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages," Nature Communications, Nature, vol. 5(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4944
    DOI: 10.1038/ncomms4944
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    Cited by:

    1. Aslihan Shenol & Ricardo Tenente & Michael Lückmann & Thomas M. Frimurer & Thue W. Schwartz, 2024. "Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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