Cell and Molecular Biology Program (M.D.R.), Institute for Integrative Toxicology (M.D.R., R.B.C., N.E.K.), Center for Research on Ingredient Safety (A.B., N.E.K.), and Departments of Microbiology and Molecular Genetics (A.A.), Osteopathic Medicine (A.A.), and Pharmacology and Toxicology (S.S., N.E.K.), Michigan State University, East Lansing, Michigan.
Cell and Molecular Biology Program (M.D.R.), Institute for Integrative Toxicology (M.D.R., R.B.C., N.E.K.), Center for Research on Ingredient Safety (A.B., N.E.K.), and Departments of Microbiology and Molecular Genetics (A.A.), Osteopathic Medicine (A.A.), and Pharmacology and Toxicology (S.S., N.E.K.), Michigan State University, East Lansing, Michigan
J Pharmacol Exp Ther. 2019 Oct;371(1):191-201. doi: 10.1124/jpet.119.260661. Epub 2019 Aug 5.
Cannabis is widely used in the United States, with an estimated prevalence of 9.5%. Certain cannabinoids in , Δ-tetrahydrocannabinol (THC) in particular, possess immune-modulating and anti-inflammatory activity. Depending on the context, the anti-inflammatory activity of cannabinoids may be beneficial (e.g., in treating inflammatory diseases) or detrimental to normal immune defense against pathogens. The potential beneficial effect of cannabinoids on chronic neuroinflammation has gained recent attention. Monocyte migration to the brain has been implicated as a key event in chronic neuroinflammation and in the etiology of central nervous system diseases including viral infection (e.g., human immunodeficiency virus-associated neurocognitive disorder). In the brain, monocytes can contribute to neuroinflammation through interactions with astrocytes, including inducing astrocyte secretion of cytokines and chemokines. In a human coculture system, monocyte-derived interleukin (IL)-1 due to Toll-like receptor 7 (TLR7) activation has been identified to promote astrocyte production of monocyte chemoattractant protein (MCP)-1 and IL-6. THC treatment of the TLR7-stimulated coculture suppressed monocyte secretion of IL-1, resulting in decreased astrocyte production of MCP-1 and IL-6. Furthermore, THC displayed direct inhibition of monocytes, as TLR7-stimulated monocyte monocultures treated with THC also showed suppressed IL-1 production. The cannabinoid receptor 2 (CB2) agonist, JWH-015, impaired monocyte IL-1 production similar to that of THC, suggesting that THC acts, in part, through CB2. THC also suppressed key elements of the IL-1 production pathway, including mRNA levels and caspase-1 activity. Collectively, this study demonstrates that the anti-inflammatory properties of THC suppress TLR7-induced monocyte secretion of IL-1 through CB2, which results in decreased astrocyte secretion of MCP-1 and IL-6. SIGNIFICANCE STATEMENT: Because cannabis use is highly prevalent in the United States and has putative anti-inflammatory properties, it is important to investigate the effect of cannabinoids on immune cell function. Furthermore, cannabinoids have garnered particular interest due to their potential beneficial effects on attenuating viral-induced chronic neuroinflammation. This study utilized a primary human coculture system to demonstrate that the major psychotropic cannabinoid in cannabis, Δ-tetrahydrocannabinol, and a cannabinoid receptor-2 selective agonist suppress specific monocyte-mediated astrocyte inflammatory responses.
大麻在美国被广泛使用，估计其流行率为 9.5%。某些大麻素，特别是 Δ-四氢大麻酚（THC），具有免疫调节和抗炎活性。根据具体情况，大麻素的抗炎活性可能有益（例如，治疗炎症性疾病），也可能对针对病原体的正常免疫防御有害。大麻素对慢性神经炎症的潜在有益作用最近引起了关注。单核细胞向大脑的迁移被认为是慢性神经炎症和包括病毒感染（例如，人类免疫缺陷病毒相关神经认知障碍）在内的中枢神经系统疾病发病机制中的关键事件。在大脑中，单核细胞可以通过与星形胶质细胞相互作用，包括诱导星形胶质细胞分泌细胞因子和趋化因子，来促进神经炎症。在人类共培养系统中，由于 Toll 样受体 7（TLR7）激活导致单核细胞衍生的白细胞介素（IL）-1 已被确定可促进星形胶质细胞产生单核细胞趋化蛋白（MCP）-1 和白细胞介素（IL）-6。TLR7 刺激共培养物中 THC 的治疗抑制了单核细胞的 IL-1 分泌，导致 MCP-1 和 IL-6 的星形胶质细胞产生减少。此外，THC 对单核细胞具有直接抑制作用，因为用 THC 处理 TLR7 刺激的单核细胞单细胞培养物也显示出 IL-1 产生受抑制。大麻素受体 2（CB2）激动剂 JWH-015 损害单核细胞 IL-1 的产生类似于 THC，表明 THC 部分通过 CB2 起作用。THC 还抑制了 IL-1 产生途径的关键元素，包括 mRNA 水平和半胱天冬酶-1 活性。总的来说，这项研究表明，THC 的抗炎特性通过 CB2 抑制 TLR7 诱导的单核细胞分泌 IL-1，从而导致 MCP-1 和 IL-6 的星形胶质细胞分泌减少。意义陈述：由于大麻在美国的使用率很高，并且具有潜在的抗炎特性，因此研究大麻素对免疫细胞功能的影响非常重要。此外，由于大麻素有减轻病毒引起的慢性神经炎症的潜在益处，因此它们受到了特别关注。本研究利用原代人共培养系统证明，大麻中的主要精神活性大麻素 Δ-四氢大麻酚和一种大麻素受体 2 选择性激动剂可抑制特定的单核细胞介导的星形胶质细胞炎症反应。
