Michigan State University, East Lansing, MI, USA.
Department of Pharmacology and Toxicology, East Lansing, MI, USA.
J Neuroimmune Pharmacol. 2020 Dec;15(4):863-874. doi: 10.1007/s11481-020-09912-z. Epub 2020 Mar 26.
CD8 T cells can contribute to neuroinflammation by secretion of inflammatory cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Astrocytes, a glial cell in the brain, can be stimulated by IFNγ and TNFα to secrete the inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and interferon-γ inducible protein 10 (IP-10). Δ-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in Cannabis sativa, possesses potent anti-inflammatory activity. The objective of this investigation was to assess the effects of THC treatment on CD8 T cell-mediated activation of astrocytes. CD3/CD28/IFNα- stimulated CD8 T cells were treated with vehicle (0.03% EtOH) or THC and cocultured with U251 astrocytes. IP-10, MCP-1, and IL-6 astrocytes were quantified by flow cytometry. LegendPlex™ was used to measure cytokine secretion by CD8 T cells and flow cytometry was employed to quantify IFNγ, TNFα, and lysosomal-associated membrane protein 1 (LAMP-1) expression. Recombinant TNFα and IFNγ were used to stimulate MCP-1, IP-10, IL-6 responses in U251 astrocytes, which were measured by flow cytometry. Treatment with THC reduced CD8 T cell-mediated induction of IP-10 and IL-6 responses in U251 astrocytes but had no effect on MCP-1. THC treatment differentially affected T cell effector functions such that IFNγ and degranulation responses were sensitive to THC-mediated ablation while TNFα was not. Lastly, THC treatment reduced the IFNγ-induced IP-10 response but had no effect on TNFα-induced MCP-1 response in U251 astrocytes. The results suggest that cannabinoid treatment can selectively reduce certain CD8 T cell responses that contribute to stimulation of astrocytes. Graphical Abstract Treatment with THC can abate CD8 T cell-dependent neuroinflammatory processes by inhibiting CD8 cell differentiation into effector cells, suppressing CD8 effector cell function, and reducing activation of astrocytes by CD8 T cell-derived inflammatory cytokines.
CD8 T 细胞可以通过分泌炎症细胞因子（如干扰素 γ（IFNγ）和肿瘤坏死因子 α（TNFα））导致神经炎症。星形胶质细胞是大脑中的神经胶质细胞，可被 IFNγ 和 TNFα 刺激分泌炎症细胞因子单核细胞趋化蛋白 1（MCP-1）、白细胞介素 6（IL-6）和干扰素-γ诱导蛋白 10（IP-10）。Δ-四氢大麻酚（THC）是大麻 sativa 中的主要精神活性大麻素，具有很强的抗炎活性。本研究的目的是评估 THC 治疗对 CD8 T 细胞介导的星形胶质细胞激活的影响。用载体（0.03% EtOH）或 THC 处理 CD3/CD28/IFNα 刺激的 CD8 T 细胞，并与 U251 星形胶质细胞共培养。通过流式细胞术定量 IP-10、MCP-1 和 IL-6 星形胶质细胞。使用 LegendPlex™ 测量 CD8 T 细胞的细胞因子分泌，并通过流式细胞术定量 IFNγ、TNFα 和溶酶体相关膜蛋白 1（LAMP-1）表达。使用重组 TNFα 和 IFNγ 刺激 U251 星形胶质细胞中的 MCP-1、IP-10 和 IL-6 反应，通过流式细胞术进行测量。THC 治疗可降低 CD8 T 细胞介导的 U251 星形胶质细胞中 IP-10 和 IL-6 反应的诱导，但对 MCP-1 没有影响。THC 治疗对 T 细胞效应功能产生不同影响，使得 IFNγ 和脱颗粒反应对 THC 介导的消融敏感，而 TNFα 则不然。最后，THC 治疗降低了 IFNγ 诱导的 U251 星形胶质细胞中 IP-10 反应，但对 TNFα 诱导的 MCP-1 反应没有影响。结果表明，大麻素治疗可通过抑制 CD8 细胞分化为效应细胞、抑制 CD8 效应细胞功能以及减少 CD8 T 细胞衍生的炎症细胞因子对星形胶质细胞的激活，选择性降低某些导致神经炎症的 CD8 T 细胞反应。
