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

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 Offermanns and Markus Schwaninger ()
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Mahbubur Rahman: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck
Sajjad Muhammad: Institute of Pharmacology, University of Heidelberg
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
Markus Schwaninger: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4944

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