BACKGROUND Lenabasum is an oral synthetic cannabinoid receptor type 2 agonist previously shown to reduce the production of key airway pro-inflammatory cytokines known to play a role in cystic fibrosis (CF). In a double-blinded, randomized, placebo-control phase 2 study, lenabasum lowered the rate of pulmonary exacerbation among patients with CF. The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum exhibits in CF macrophages. METHODS We used monocyte-derived macrophages (MDMs) from healthy donors (n = 15), MDMs with CFTR inhibited with C-172 (n = 5) and MDMs from patients with CF (n = 4). Monocytes were differentiated to macrophages and polarized into classically activated (M1) macrophages by LPS or alternatively activated (M2) macrophages by IL-13 in presence or absence of lenabasum. RESULTS Lenabasum had no effect on differentiation, polarization and function of macrophages from healthy individuals. However, in CF macrophages lenabasum downregulated macrophage polarization into the pro-inflammatory M1 phenotype and secretion of the pro-inflammatory cytokines IL-8 and TNF-α in a dose-dependent manner. An improvement in phagocytic activity was also observed following lenabasum treatment. Although lenabasum did not restore the impaired polarization of anti-inflammatory M2 macrophage, it reduced the levels of IL-13 and enhanced the endocytic function of CF MDMs. The effects of lenabasum on MDMs with CFTR inhibited by C-172 were not as obvious. CONCLUSION In CF macrophages lenabasum modulates macrophage polarization and function in vitro in a way that would reduce inflammation in vivo. Further studies are warranted to determine the link between activating the CBR2 receptor and CFTR.

中文翻译：

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大麻素受体 2 型激动剂 lenabasum 对囊性纤维化巨噬细胞的抗炎作用。

背景 Lenabasum 是一种口服合成大麻素受体 2 型激动剂，先前已证明可减少已知在囊性纤维化 (CF) 中起作用的关键气道促炎细胞因子的产生。在一项双盲、随机、安慰剂对照的 2 期研究中，lenabasum 降低了 CF 患者的肺部恶化率。本研究旨在调查 CF 巨噬细胞中 lenabasum 展品的抗炎机制。方法我们使用来自健康供体（n = 15）的单核细胞衍生的巨噬细胞（MDM）、C-172抑制CFTR的MDM（n = 5）和来自CF患者的MDM（n = 4）。单核细胞分化为巨噬细胞，并通过 LPS 极化为经典激活的 (M1) 巨噬细胞，或在 lenabasum 存在或不存在的情况下通过 IL-13 激活 (M2) 巨噬细胞。结果 Lenabasum 对健康个体巨噬细胞的分化、极化和功能没有影响。然而，在 CF 巨噬细胞中，lenabasum 以剂量依赖性方式将巨噬细胞极化下调为促炎 M1 表型和促炎细胞因子 IL-8 和 TNF-α 的分泌。在lenabasum治疗后也观察到吞噬活性的改善。尽管 lenabasum 没有恢复抗炎 M2 巨噬细胞受损的极化，但它降低了 IL-13 的水平并增强了 CF MDM 的内吞功能。lenabasum 对 C-172 抑制 CFTR 的 MDM 的影响不那么明显。结论 在 CF 巨噬细胞中，lenabasum 在体外调节巨噬细胞极化和功能，以减少体内炎症。