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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents



ID: 711872.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
The beta-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages
Authors:Rahman, M.; Muhammad, S.; Khan, M. A.; Chen, H.; Ridder, D. A.; Muller-Fielitz, H.; Pokorna, B.; Vollbrandt, T.; Stolting, I.; Nadrowitz, R.; Okun, J. G.; Offermanns, S.; Schwaninger, M.
Date of Publication (YYYY-MM-DD):2014
Title of Journal:Nat Commun
Volume:5
Start Page:3944
Audience:Not Specified
Abstract / Description:The ketone body beta-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.
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:1] Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany [2] [3]. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany. Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Institute for Systemic Inflammation Research, University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany. Institute of Radiotherapy and Nuclear Medicine, University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany. Department of Pediatrics, University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. 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. 1] Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany [2] DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany. %^ 1435822116
Identifiers:ISSN:2041-1723 (Electronic) 2041-1723 (Linking) %R 10.1038/ncomms4944
URL:http://www.ncbi.nlm.nih.gov/pubmed/24845831
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