title: Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism.
abstract: Cerebral malaria is a severe and often fatal complication of Plasmodium falciparum infection. It is characterized by parasite sequestration, a breakdown of the blood-brain barrier, and a strong inflammation in the brain. We investigated the role of the cannabinoid receptor 2 (CB2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ECM). Strikingly, mice with a deletion of the CB2-encoding gene (Cnr2(-/-)) inoculated with Plasmodium berghei ANKA erythrocytes exhibited enhanced survival and a diminished blood-brain barrier disruption. Therapeutic application of a specific CB2 antagonist also conferred increased ECM resistance in wild type mice. Hematopoietic derived immune cells were responsible for the enhanced protection in bone marrow (BM) chimeric Cnr2(-/-) mice. Mixed BM chimeras further revealed that CB2-expressing cells contributed to ECM development. A heterogeneous CD11b(+) cell population, containing macrophages and neutrophils, expanded in the Cnr2(-/-) spleen after infection and expressed macrophage mannose receptors, arginase-1 activity, and IL-10. Also in the Cnr2(-/-) brain, CD11b(+) cells that expressed selected anti-inflammatory markers accumulated, and expression of inflammatory mediators IFN-γ and TNF-α was reduced. Finally, the M2 macrophage chemokine CCL17 was identified as an essential factor for enhanced survival in the absence of CB2, because CCL17 × Cnr2 double-deficient mice were fully susceptible to ECM. Thus, targeting CB2 may be promising for the development of alternative treatment regimes of ECM.
authors.affiliation: From the Institute of Molecular Psychiatry, Medical Faculty, and the Department of Psychiatry, University of Münster, 48149 Münster, Germany, the Cluster of Excellence EXC 1003, Cells in Motion, 48149 Münster, Germany, Judith.alferink@ukmuenster.de.
authors.forename: Judith
authors.initials: J
authors.lastname: Alferink
authors.affiliation: the Institute of Medical Microbiology, Immunology, and Parasitology and.
authors.forename: Sabine
authors.initials: S
authors.lastname: Specht
authors.affiliation: From the Institute of Molecular Psychiatry, Medical Faculty, and.
authors.forename: Hannah
authors.initials: H
authors.lastname: Arends
authors.affiliation: the Institute of Medical Microbiology, Immunology, and Parasitology and.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Schumak
authors.affiliation: the Institute of Medical Microbiology, Immunology, and Parasitology and.
authors.forename: Kim
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: the Department of Psychiatry, University of Münster, 48149 Münster, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Ruland
authors.affiliation: From the Institute of Molecular Psychiatry, Medical Faculty, and.
authors.forename: Ramona
authors.initials: R
authors.lastname: Lundt
authors.affiliation: From the Institute of Molecular Psychiatry, Medical Faculty, and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kemter
authors.affiliation: the Department of Psychiatry, University of Münster, 48149 Münster, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dlugos
authors.affiliation: the Institute of Medical Microbiology, Immunology, and Parasitology and.
authors.forename: Janina M
authors.initials: JM
authors.lastname: Kuepper
authors.affiliation: From the Institute of Molecular Psychiatry, Medical Faculty, and.
authors.forename: Karola
authors.initials: K
authors.lastname: Poppensieker
authors.affiliation: From the Institute of Molecular Psychiatry, Medical Faculty, and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Findeiss
authors.affiliation: From the Institute of Molecular Psychiatry, Medical Faculty, and.
authors.forename: Önder
authors.initials: Ö
authors.lastname: Albayram
authors.affiliation: From the Institute of Molecular Psychiatry, Medical Faculty, and.
authors.forename: David-M
authors.initials: DM
authors.lastname: Otte
authors.affiliation: the Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland, and.
authors.forename: Janine
authors.initials: J
authors.lastname: Marazzi
authors.affiliation: the Institute of Biochemistry and Molecular Medicine, University of Bern, 3012 Bern, Switzerland, and.
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
authors.affiliation: the Department of Immunology and Environment, Life and Medical Sciences Institute (LIMES), University of Bonn, 53127 Bonn, Germany.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Förster
authors.affiliation: the Department of Psychiatry, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.affiliation: the Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scheu
authors.affiliation: the Institute of Medical Microbiology, Immunology, and Parasitology and.
authors.forename: Achim
authors.initials: A
authors.lastname: Hoerauf
authors.affiliation: From the Institute of Molecular Psychiatry, Medical Faculty, and neuro@uni-bonn.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000276:immunology; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D054414:Chemokine CCL17 / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D016779:Malaria, Cerebral / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010962:Plasmodium berghei / Q000276:immunology*; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology
chemical_list: C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; C571431:Cnr2 protein, mouse; C556062:IL10 protein, mouse; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D043885:Receptor, Cannabinoid, CB2; D011956:Receptors, Cell Surface; D016753:Interleukin-10; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: chemokine; endocannabinoid; macrophage; malaria; neuroinflammation