Role of the cannabinoid receptor 2 (CB2) in neuroinflammation
Zusammenfassung der Projektergebnisse
The cannabinoid receptor 2 (CB2) is an important modulator of neuroinflammatory responses, albeit its role in cerebral malaria (CM) has not been studied yet. CM is a life-threatening complication of the Plasmodium falciparum infection and one of the world leading causes of mortality. CM can be modeled in mice through infection with P. berghei ANKA carrying red blood cells (PbA-RBCs). The aim of the study proposed was to investigate the functional role of CB2 in experimental cerebral malaria (ECM). This project was based on our earlier findings that CB2 knockout (Cnr2-/-) mice inoculated with Plasmodium berghei ANKA-erythrocytes exhibited enhanced survival and a diminished blood-brain-barrier disruption. Utilizing Cnr2-/- and cell specific knockout mice, the generation of mixed BM-chimeras and a pharmacological approach we aimed to study myeloid cell responses mediating CB2 dependent effects in this inflammatory CNS disorder. By generation and analysis of mixed bone-marrow-chimeras we could show that the effector cells mediating enhanced protection to ECM in Cnr2-/- mice were myeloid but not lymphoid cells. We further determined enhanced percentages of myeloid CD11b+ cells in the spleens as well as in the brains of infected Cnr2-/- mice. Myeloid cell infiltrates in PbA-infected Cnr2-/- mice were composed mainly of CD11b+ macrophages, but not of dendritic cell subsets or neutrophils. We could further demonstrate that CD11b+ macrophages in infected Cnr2-/- mice exhibited an anti-inflammatory phenotype and function. These cells expressed enhanced levels of anti-inflammatory macrophage mannose receptors (MMR). In addition, anti-inflammatory cytokine IL-10 expression and arginase-1 activity was enhanced in these cells indicating that they exerted protective functions after PbA-infection. Accordingly, brain infiltrates of Cnr2-/- mice contained increased percentages of Ly6Chigh CD11b+ myeloid cells that expressed enhanced MMR and arginase-1, distinctive markers of anti-inflammatory macrophage functions. We could further show, that purified Cnr2-/- CD8+ T cells from the spleens of infected Cnr2-/- mice were capable of producing cytolytic factors when restimulated with peptide presented by CB2-competent antigen presenting cells. Thus, CB2 does not affect CD8 T cell function in a cell-intrinsic way, but alters myeloid-derived cell functions and their ability to induce factors in CD8 T cells required for ECM induction. In summary we have shown that CB2 mediates detrimental effects in a mouse model of CM by modulating macrophage effector functions during the anti-infectious immune response of the CNS. Thus, targeting CB2 may be promising for the development of alternative treatment regimes of parasite encephalitis.
Projektbezogene Publikationen (Auswahl)
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2012. CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells. Proc Natl Acad Sci USA 109:3897-902
Poppensieker K., D.M. Otte, B. Schürmann, A. Limmer, P. Dresing, E. Drews, B. Schumak, L. Klotz, J. Raasch, A. Mildner, A. Waisman, S. Scheu, P. Knolle, I. Förster, M. Prinz, W. Maier, A. Zimmer, and J. Alferink
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2014. The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy. Basic Res Cardiol. 2014 Jul;109(4):425
Duerr GD, Heinemann JC, Suchan G, Kolobara E, Wenzel D, Geisen C, Matthey M, Passe-Tietjen K, Mahmud W, Ghanem A, Tiemann K, Alferink J, Burgdorf S, Buchalla R, Zimmer A, Lutz B, Welz A, Fleischmann BK, Dewald O
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2015. Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer's disease mouse model. Neurobiol Aging. Feb;36(2):710-9
Schmöle AC, Lundt R, Ternes S, Albayram Ö, Ulas T, Schultze JL, Bano D, Nicotera P, Alferink J, Zimmer A
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2015. The cannabinoid receptor 2 is involved in acute rejection of cardiac allografts. Life Sci. Oct 1;138:29-34
Kemter AM, Scheu S, Hüser N, Ruland C, Schumak B, Findeiß M, Cheng Z, Assfalg V, Arolt V, Zimmer A, Alferink J
