Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, University of Dublin, Dublin, Ireland.
GW Research Ltd, Sovereign House, Vision Park, Histon, CB24 9BZ, United Kingdom.
J Neuroimmunol. 2020 Jun 15;343:577217. doi: 10.1016/j.jneuroim.2020.577217. Epub 2020 Mar 20.
Toll-like receptors (TLRs) are sensors of pathogen-associated molecules that trigger inflammatory signalling in innate immune cells including macrophages. All TLRs, with the exception of TLR3, promote intracellular signalling via recruitment of the myeloid differentiation factor 88 (MyD88) adaptor, while TLR3 signals via Toll-Interleukin-1 Receptor (TIR)-domain-containing adaptor-inducing interferon (IFN)-β (TRIF) adaptor to induce MyD88-independent signalling. Furthermore, TLR4 can activate both MyD88-dependent and -independent signalling (via TRIF). The study aim was to decipher the impact of the highly purified plant-derived (phyto) cannabinoids Δ-tetrahydrocannabinol (THC) and cannabidiol (CBD), when delivered in isolation and in combination (1:1), on MyD88-dependent and -independent signalling in macrophages. We employed the use of the viral dsRNA mimetic poly(I:C) and endotoxin lipopolysaccharide (LPS), to induce viral TLR3 and bacterial TLR4 signalling in human Tamm-Horsfall protein-1 (THP-1)-derived macrophages, respectively. TLR3/TLR4 stimulation promoted the activation of interferon (IFN) regulatory factor 3 (IRF3) and TLR4 promoted the activation of nuclear factor (NF)-κB signalling, with downstream production of the type I IFN-β, the chemokines CXCL10 and CXCL8, and cytokine TNF-α. THC and CBD (both at 10 μM) attenuated TLR3/4-induced IRF3 activation and induction of CXCL10/IFN-β, while both phytocannabinoids failed to impact TLR4-induced IκB-α degradation and TNF-α/CXCL8 expression. The role of CB, CB and PPARγ receptors in mediating the effect of THC and CBD on MyD88-independent signalling was investigated. TLRs are attractive therapeutic targets given their role in inflammation and initiation of adaptive immunity, and data herein indicate that both CBD and THC preferentially modulate TLR3 and TLR4 signalling via MyD88-independent mechanisms in macrophages. This offers mechanistic insight into the role of phytocannabinoids in modulating cellular inflammation.
Toll 样受体 (TLRs) 是病原体相关分子的传感器，可在包括巨噬细胞在内的固有免疫细胞中触发炎症信号。除 TLR3 外，所有 TLR 均通过髓样分化因子 88 (MyD88) 衔接子募集来促进细胞内信号转导，而 TLR3 通过 Toll-白细胞介素-1 受体 (TIR) 结构域包含衔接子诱导干扰素 (IFN)-β (TRIF) 衔接子诱导 MyD88 非依赖性信号转导。此外，TLR4 可以激活 MyD88 依赖性和非依赖性信号转导 (通过 TRIF)。本研究旨在阐明高度纯化的植物源性 (植物) 大麻素 Δ-四氢大麻酚 (THC) 和大麻二酚 (CBD) 在单独和联合 (1:1) 给药时对巨噬细胞中 MyD88 依赖性和非依赖性信号转导的影响。我们使用病毒双链 RNA 模拟物聚 (I:C) 和内毒素脂多糖 (LPS) 分别诱导人 Tamm-Horsfall 蛋白-1 (THP-1) 衍生的巨噬细胞中的病毒 TLR3 和细菌 TLR4 信号转导。TLR3/TLR4 刺激促进干扰素 (IFN) 调节因子 3 (IRF3) 的激活，TLR4 促进核因子 (NF)-κB 信号转导的激活，下游产生 I 型 IFN-β、趋化因子 CXCL10 和 CXCL8 以及细胞因子 TNF-α。THC 和 CBD(均为 10 μM) 减弱 TLR3/4 诱导的 IRF3 激活和 CXCL10/IFN-β 的诱导，而两种植物大麻素均未能影响 TLR4 诱导的 IκB-α 降解和 TNF-α/CXCL8 的表达。研究了 CB、CB 和 PPARγ 受体在介导 THC 和 CBD 对 MyD88 非依赖性信号转导的作用。鉴于 TLR 在炎症和适应性免疫启动中的作用，TLRs 是有吸引力的治疗靶点，本文数据表明，CBD 和 THC 均优先通过巨噬细胞中 MyD88 非依赖性机制调节 TLR3 和 TLR4 信号转导。这为植物大麻素在调节细胞炎症中的作用提供了机制上的见解。
