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(Cb2)在慢性疼痛的神经炎症过程中控制干扰素-γ反应和小胶质细胞激活的影响。由于已知这两个免疫过程都影响寄生虫性脑炎的发病机制，我们还研究了脑型疟疾(CM)和弓形虫脑炎(TE)中的CB2信号。伯氏疟原虫(PBA)感染的CB2基因敲除(Cnr2-/-)小鼠的存活率提高，而所有野生型(WT)对照小鼠都死于疾病。在感染Cnr2-/-小鼠中发现的血管隔离减少和血脑屏障完整可能导致抵抗力增强。此外，CNR2-/-动物的神经炎性反应减弱，CNS迁移的CD8T细胞和活化的髓系细胞数量减少。重要的是，CB2拮抗剂SR122458的治疗应用增强了C57BL/6小鼠对CM的抵抗力。在弓形虫感染的Cnr2-/-小鼠中，进一步证明了CB2在TE免疫发病机制中的功能作用，表现出更高的死亡率。在这里，我们计划通过评估Cnr2-/-和骨髓嵌合小鼠以及基于CB2的药理学方法来研究寄生虫性脑炎中CB2介导的潜在免疫机制。为了剖析CB2信号在淋巴细胞和/或髓系细胞在神经炎症中的具体作用，我们将研究细胞特异性CB2条件性基因敲除小鼠。我们的目标是确定新的CB2依赖机制，具有控制神经炎性反应的治疗潜力。

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.