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Nat Commun. 2014 May 21;5:3944. doi: 10.1038/ncomms4944.

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

Author information

1
1] Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany [2].
2
1] Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany [2] [3].
3
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
4
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
5
Institute for Systemic Inflammation Research, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
6
Institute of Radiotherapy and Nuclear Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
7
Department of Pediatrics, University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
8
1] Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany [2] Medical Faculty, Goethe University, Frankfurt, Germany.
9
1] Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany [2] DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany.

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-6C(Lo) 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-6C(Lo) monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

PMID:
24845831
DOI:
10.1038/ncomms4944
[Indexed for MEDLINE]

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