Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, 07743 Jena, Germany.
Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
Cell Chem Biol. 2023 Dec 21;30(12):1508-1524.e7. doi: 10.1016/j.chembiol.2023.08.001. Epub 2023 Aug 29.
Cannabinoids are phytochemicals from cannabis with anti-inflammatory actions in immune cells. Lipid mediators (LM), produced from polyunsaturated fatty acids (PUFA), are potent regulators of the immune response and impact all stages of inflammation. How cannabinoids influence LM biosynthetic networks is unknown. Here, we reveal cannabidiol (CBD) as a potent LM class-switching agent that stimulates the production of specialized pro-resolving mediators (SPMs) but suppresses pro-inflammatory eicosanoid biosynthesis. Detailed metabololipidomics analysis in human monocyte-derived macrophages showed that CBD (i) upregulates exotoxin-stimulated generation of SPMs, (ii) suppresses 5-lipoxygenase (LOX)-mediated leukotriene production, and (iii) strongly induces SPM and 12/15-LOX product formation in resting cells by stimulation of phospholipase A-dependent PUFA release and through Ca-independent, allosteric 15-LOX-1 activation. Finally, in zymosan-induced murine peritonitis, CBD increased SPM and 12/15-LOX products and suppressed pro-inflammatory eicosanoid levels in vivo. Switching eicosanoid to SPM production is a plausible mode of action of CBD and a promising inflammation-resolving strategy.
大麻素是大麻中的植物化学物质，具有免疫细胞的抗炎作用。脂类介质（LM）是由多不饱和脂肪酸（PUFA）产生的，是免疫反应的有效调节剂，影响炎症的所有阶段。大麻素如何影响 LM 生物合成网络尚不清楚。在这里，我们发现大麻二酚（CBD）是一种有效的 LM 类别转换剂，可刺激专门的促解决介质（SPM）的产生，但抑制促炎类二十烷酸生物合成。对人单核细胞衍生的巨噬细胞进行的详细代谢脂质组学分析表明，CBD（i）上调外毒素刺激的 SPM 生成，（ii）抑制 5-脂氧合酶（LOX）介导的白三烯产生，以及（iii）通过刺激磷脂酶 A 依赖性 PUFA 释放和通过 Ca 独立的变构 15-LOX-1 激活，强烈诱导静止细胞中 SPM 和 12/15-LOX 产物的形成。最后，在酵母聚糖诱导的小鼠腹膜炎中，CBD 增加了 SPM 和 12/15-LOX 产物，并抑制了体内的促炎类二十烷酸水平。将类二十烷酸转化为 SPM 产生是 CBD 的一种合理作用模式，也是一种有前途的炎症缓解策略。
