Role of the cannabinoid receptor 2 (CB2) in neuroinflammation

我们以前的工作证明了大麻素受体2（CB 2）在慢性疼痛神经炎症过程中控制IFN- γ反应和小胶质细胞活化的影响。由于这两个免疫过程是已知的影响寄生虫引起的脑炎的发病机制，我们还研究了CB 2信号在脑型疟疾（CM）和弓形虫脑炎（TE）。伯氏疟原虫ANKA（PbA）感染的CB 2敲除（Cnr 2-/-）小鼠表现出增强的存活率，而所有野生型（WT）对照都死于疾病。在感染的Cnr 2-/-小鼠中鉴定的减少的血管隔离和完整的血脑屏障可能导致抗性增加。此外，减少的神经炎症反应发生在Cnr 2-/-动物中，CNS-迁移的CD 8 T细胞和活化的骨髓细胞的数量减少。重要的是，CB 2拮抗剂SR 122458的治疗应用赋予C57 BL/6小鼠增强的CM抗性。CB 2在TE免疫发病机制中的功能作用在T.显示出增加的死亡率的刚地氏菌感染的Cnr 2-/-小鼠。在这里，我们计划通过评估Cnr 2-/-和骨髓嵌合小鼠和基于CB 2的药理学方法来研究寄生虫脑炎中CB 2介导的免疫机制。为了剖析CB 2信号传导在神经炎症期间在淋巴细胞和/或骨髓细胞中的特定作用，将研究细胞特异性CB 2条件性敲除小鼠。我们的目的是确定新的CB 2依赖性机制与治疗潜力参与控制神经炎症反应。

Our previous work demonstrated the impact of the cannabinoid receptor 2 (CB2) in the control of IFN- γ responses and microglial activation during neuroinflammation in chronic pain. Since both immune processes are known to influence the pathogenesis of parasite-induced encephalitis, we also investigated CB2 signaling in cerebral malaria (CM) and Toxoplasma gondii encephalitis (TE). Plasmodium berghei ANKA (PbA)-infected CB2 knockout (Cnr2-/-) mice exhibit enhanced survival, while all wild type (WT) controls succumb to disease. A reduced blood vessel sequestration and an intact blood brain barrier identified in infected Cnr2-/- mice could cause increased resistance. In addition, diminished neuroinflammatory responses occur in Cnr2-/- animals with reduced numbers of CNS-immigrated CD8 T cells and activated myeloid cells. Importantly, therapeutic application of the CB2 antagonist SR122458 confers enhanced CM resistance in C57BL/6 mice. A functional role of CB2 in the immunopathogenesis of TE was further demonstrated in T. gondii-infected Cnr2-/- mice which exhibit enhanced mortality. Here we plan to investigate the underlying CB2-mediated immune mechanisms in parasite encephalitis by assessing Cnr2-/- and bone-marrow-chimeric mice and CB2- based pharmacological approaches. To dissect the specific roles of CB2 signaling in lymphocytes and/or myeloid cells during neuroinflammation, cell-specific CB2 conditional knockout mice will be investigated. We aim to define novel CB2-dependent mechanisms with therapeutic potential involved in the control of neuroinflammatory responses.