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Induction of a neuroprotective phenotype of macrophages by the β-hydroxybutyrate receptor HCA2

Rahman, Md. Mahbubur

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Ketogenic diet is protective in models of ischemic stroke and neurodegenerative diseases. Currently, clinical trials are testing the efficacy of this diet in neurodegenerative diseases but its mode of action is still unclear. The ketone body β-hydroxybutyrate (BHB) is the endogenous agonist of the hydroxy-carboxylic acid receptor 2 (HCA2, GPR109A) which is expressed in various immune cells; therefore, we tested the potential involvement of this receptor in a mouse model of ischemic stroke. The protective effect of ketogenic diet and BHB was lost in Hca2-/- mice, demonstrating that HCA2 receptors are responsible for neuroprotection. Similarly, nicotinic acid, a HCA2 agonist, reduced the infarct size via a HCA2-mediated mechanism. Immunohistochemical analysis of immune cells in Hca2mRFP transgenic mice revealed HCA2 expression in monocytes/macrophages. Bone marrow transplantation demonstrated that HCA2 on monocytes/macrophages is required for the protective effect. Activation of HCA2 receptors induced a neuroprotective phenotype of monocytes/macrophages that depended on PGD2 production by COX-1 and the hematopoietic PGD2 synthase. Our data reveal that HCA2 activation by dietary or pharmacological means instructs monocytes/macrophages to carry a neuroprotective signal to the brain which can be used therapeutically.

Item Type: Dissertation
Supervisor: Schwaninger, Prof. Dr. Markus
Publisher: University of Heidelberg press
Place of Publication: Heidelberg
Date of thesis defense: 17 September 2013
Date Deposited: 11 Oct 2013 09:12
Date: 2013
Faculties / Institutes: The Faculty of Bio Sciences > Institute of Pharmacy and Molecular Biotechnology
Subjects: 500 Natural sciences and mathematics
570 Life sciences
610 Medical sciences Medicine
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