Cannabinoid Receptor 2 Modulates Susceptibility to Experimental Cerebral Malaria through a CCL17-dependent Mechanism

Judith Alferink,Andrea Dlugos,Achim Hoerauf,Janina M Kuepper,Janine Marazzi,David-M Otte,Jürg Gertsch,Hannah Arends,Sabine Specht,Beatrix Schumak,Irmgard Förster,Karola Poppensieker,Ramona Lundt,Andreas Zimmer,Wolfgang Maier,Christina Ruland,Stefanie Scheu,Önder Albayram,Kim E Schmidt ,Matthias Findeiß ,Andrea M Kemter

doi:10.1074/jbc.m116.746594

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.

Highlights

Cerebral malaria is a severe and often fatal complication of Plasmodium falciparum infection
We investigated the role of the cannabinoid receptor 2 (CB2), an important modulator of neuroinflammatory responses, in experimental cerebral malaria (ECM)
Enhanced Protection of Cnr2Ϫ/Ϫ Mice against ECM Is Mediated by Immune Cells—We studied different components of the endocannabinoid system after Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice [20, 24]

Summary

Introduction

Cerebral malaria is a severe and often fatal complication of Plasmodium falciparum infection. The absolute number of mononuclear brain-infiltrating cells was markedly reduced in Cnr2Ϫ/Ϫ mice at day 6 after PbA infection (Fig. 2A). These data indicate that CB2 does not affect basic T cell priming properties of BM DCs. M-CSF-generated CD11bϩ BM macrophages from Cnr2Ϫ/Ϫ mice expressed enhanced Ym1 and arginase-1 (Arg-1) mRNA levels under IL-4-stimulatory conditions (Fig. 3C).

Results

Conclusion