Alferink Judith, Specht Sabine, Arends Hannah, Schumak Beatrix, Schmidt Kim, Ruland Christina, Lundt Ramona, Kemter Andrea, Dlugos Andrea, Kuepper Janina M, Poppensieker Karola, Findeiss Matthias, Albayram Önder, Otte David-M, Marazzi Janine, Gertsch Jürg, Förster Irmgard, Maier Wolfgang, Scheu Stefanie, Hoerauf Achim, Zimmer Andreas
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,
the Institute of Medical Microbiology, Immunology, and Parasitology and.
J Biol Chem. 2016 Sep 9;291(37):19517-31. doi: 10.1074/jbc.M116.746594. Epub 2016 Jul 29.
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.
脑型疟疾是恶性疟原虫感染的一种严重且通常致命的并发症。其特征为寄生虫滞留、血脑屏障破坏以及脑部强烈炎症。我们研究了大麻素受体2（CB2），一种神经炎症反应的重要调节因子，在实验性脑型疟疾（ECM）中的作用。令人惊讶的是，接种伯氏疟原虫ANKA红细胞的CB2编码基因缺失（Cnr2(-/-)）小鼠存活率提高，血脑屏障破坏减轻。特异性CB2拮抗剂的治疗应用也使野生型小鼠对ECM的抵抗力增强。造血来源的免疫细胞负责骨髓（BM）嵌合Cnr2(-/-)小鼠的增强保护作用。混合骨髓嵌合体进一步表明，表达CB2的细胞促成了ECM的发展。感染后，Cnr2(-/-)脾脏中包含巨噬细胞和中性粒细胞的异质性CD11b(+)细胞群体扩增，并表达巨噬细胞甘露糖受体、精氨酸酶-1活性和IL-10。同样在Cnr2(-/-)脑中，表达选定抗炎标志物的CD11b(+)细胞积聚，炎症介质IFN-γ和TNF-α的表达降低。最后，M2巨噬细胞趋化因子CCL17被确定为在缺乏CB2时提高存活率的关键因素，因为CCL17×Cnr2双缺陷小鼠对ECM完全易感。因此，靶向CB2可能为开发ECM的替代治疗方案带来希望。
