Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism
| Autor: | Kim E. Schmidt, Beatrix Schumak, David-M. Otte, Janina M. Kuepper, Sabine Specht, Hannah Arends, Irmgard Förster, Judith Alferink, Ramona Lundt, Stefanie Scheu, Andreas Zimmer, Janine Marazzi, Matthias Findeiss, Christina Ruland, Onder Albayram, Wolfgang Maier, Andrea Dlugos, Andrea M. Kemter, Achim Hoerauf, Karola Poppensieker, Jürg Gertsch |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Chemokine Neutrophils Plasmodium berghei Immunology Malaria Cerebral Inflammation Receptors Cell Surface Biochemistry Receptor Cannabinoid CB2 03 medical and health sciences Mice 0302 clinical medicine Immune system Cannabinoid receptor type 2 medicine Animals Lectins C-Type 610 Medicine & health Molecular Biology Mice Knockout biology Arginase Macrophages Cell Biology M2 Macrophage biology.organism_classification Molecular biology Interleukin-10 Interleukin 10 Disease Models Animal 030104 developmental biology Mannose-Binding Lectins Cerebral Malaria Blood-Brain Barrier biology.protein 570 Life sciences Female lipids (amino acids peptides and proteins) Chemokine CCL17 Disease Susceptibility medicine.symptom Mannose Receptor 030215 immunology |
| DOI: | 10.7892/boris.94102 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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