Department of Anesthesiology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
Institute of Doping Analysis and Sports Biochemistry, Kreischa, Germany.
Cannabis Cannabinoid Res. 2024 Oct;9(5):1326-1338. doi: 10.1089/can.2023.0040. Epub 2023 Sep 14.
Endocannabinoids in COVID-19 have immunomodulatory and anti-inflammatory properties but the functional role and the regulation of endocannabinoid signaling in this pandemic disorder is controversial. To exercise their biologic function, endocannabinoids need to travel across the intercellular space and within the blood stream to reach their target cells. How the lipophilic endocannabinoids are transported in the vascular system and how these hydrophobic compounds cross cell membranes is still unclear. Extracellular vesicles (EVs) are released and incorporated by many cell types including immune cells. EVs are small lipid-membrane covered particles and contain RNA, lipids and proteins. They play an important role in intercellular communication by transporting these signaling molecules from their cells of origin to specific target cells. EVs may represent ideal transport vehicles for lipophilic signaling molecules like endocannabinoids and this effect could also be evident in COVID-19. We measured the endocannabinoids anandamide, 2-AG, SEA, PEA and OEA in patients with COVID-19 in EVs and plasma. RNA sequencing of microRNAs (miRNAs) derived from EVs (EV-miRNAs) and mRNA transcripts from blood cells was used for the construction of signaling networks reflecting endocannabinoid and miRNA communication by EVs to target immune cells. With the exception of anandamide, endocannabinoid concentrations were significantly enriched in EVs in comparison to plasma and increased with disease severity. No enrichment in EVs was seen for the more hydrophilic steroid hormones cortisol and testosterone. High EV-endocannabinoid concentrations were associated with downregulation of CNR2 (CB2) by upregulated EV-miRNA miR-146a-5p and upregulation of MGLL by downregulated EV-miR-199a-5p and EV-miR-370-5p suggesting counterregulatory effects. In contrast, low EV-levels of anandamide were associated with upregulation of CNR1 by downregulation of EV-miR-30c-5p and miR-26a-5p along with inhibition of FAAH. Immunologically active molecules in immune cells regulated by endocannabinoid signaling included VEGFA, GNAI2, IGF1, BDNF, IGF1R and CREB1 and CCND1 among others. EVs carry immunologically functional endocannabinoids in COVID-19 along with miRNAs which may regulate the expression of mRNA transcripts involved in the regulation of endocannabinoid signaling and metabolism. This mechanism could fine-tune and adapt endocannabinoid effects in recipient cells in relationship to the present biological context.
内源性大麻素在 COVID-19 中具有免疫调节和抗炎作用，但内源性大麻素信号在这种大流行疾病中的功能作用和调节仍存在争议。为了发挥其生物学功能，内源性大麻素需要穿越细胞间隙并在血流中运输，以到达靶细胞。亲脂性内源性大麻素如何在血管系统中运输，以及这些疏水分子如何穿过细胞膜，目前仍不清楚。细胞外囊泡（EVs）是许多细胞类型（包括免疫细胞）释放和摄取的小的脂质膜包裹的颗粒，包含 RNA、脂质和蛋白质。它们通过将这些信号分子从其来源细胞运输到特定的靶细胞，在细胞间通讯中发挥重要作用。EVs 可能是亲脂性信号分子（如内源性大麻素）的理想运输载体，这种效应在 COVID-19 中也可能很明显。我们测量了 COVID-19 患者 EVs 和血浆中的内源性大麻素（AEA）、2-AG、SEA、PEA 和 OEA。从 EVs（EV-miRNAs）中提取的 microRNAs（miRNAs）的 RNA 测序和血液细胞中的 mRNA 转录物被用于构建反映 EV 对内源性大麻素和 miRNA 与免疫细胞通讯的信号网络。除了 AEA 之外，内源性大麻素浓度在 EVs 中的富集程度明显高于血浆，并且随着疾病严重程度的增加而增加。亲水性甾体激素皮质醇和睾酮在 EVs 中没有富集。高 EV-内源性大麻素浓度与 CNR2（CB2）的下调有关，这是由上调的 EV-miRNA miR-146a-5p 引起的，与下调的 EV-miR-199a-5p 和 EV-miR-370-5p 引起的 MGLL 上调有关，提示存在反调节作用。相比之下，低 EV 水平的 AEA 与 CNR1 的上调有关，这是由 EV-miR-30c-5p 和 miR-26a-5p 的下调以及 FAAH 的抑制引起的。受内源性大麻素信号调节的免疫细胞中的免疫活性分子包括 VEGFA、GNAI2、IGF1、BDNF、IGF1R 和 CREB1 以及 CCND1 等。EVs 在 COVID-19 中携带具有免疫功能的内源性大麻素，以及可能调节内源性大麻素信号和代谢相关的 mRNA 转录物表达的 miRNA。这种机制可以根据当前的生物学背景，精细调节和适应内源性大麻素在受体细胞中的作用。
