Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital, Tianjin, China.
Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital, Tianjin, China; Graduate School, Tianjin Medical University, Tianjin, China.
Cell Signal. 2023 Sep;109:110768. doi: 10.1016/j.cellsig.2023.110768. Epub 2023 Jun 12.
Acute lung injury is significantly associated with the aberrant activation and pyroptosis of alveolar macrophages. Targeting the GPR18 receptor presents a potential therapeutic approach to mitigate inflammation. Verbenalin, a prominent component of Verbena in Xuanfeibaidu (XFBD) granules, is recommended for treating COVID-19. In this study, we demonstrate the therapeutic effect of verbenalin on lung injury through direct binding to the GPR18 receptor. Verbenalin inhibits the activation of inflammatory signaling pathways induced by lipopolysaccharide (LPS) and IgG immune complex (IgG IC) via GPR18 receptor activation. The structural basis for verbenalin's effect on GPR18 activation is elucidated through molecular docking and molecular dynamics simulations. Furthermore, we establish that IgG IC induces macrophage pyroptosis by upregulating the expression of GSDME and GSDMD through CEBP-δ activation, while verbenalin inhibits this process. Additionally, we provide the first evidence that IgG IC promotes the formation of neutrophil extracellular traps (NETs), and verbenalin suppresses NETs formation. Collectively, our findings indicate that verbenalin functions as a "phytoresolvin" to promote inflammation regression and suggests that targeting the C/EBP-δ/GSDMD/GSDME axis to inhibit macrophage pyroptosis may represent a novel strategy for treating acute lung injury and sepsis.
急性肺损伤与肺泡巨噬细胞的异常激活和细胞焦亡显著相关。靶向 GPR18 受体为减轻炎症提供了一种潜在的治疗方法。马鞭草苷是玄肺败毒颗粒（XFBD）中马鞭草的主要成分之一，被推荐用于治疗 COVID-19。在这项研究中，我们通过直接与 GPR18 受体结合，证明了马鞭草苷对肺损伤的治疗作用。马鞭草苷通过 GPR18 受体的激活，抑制脂多糖（LPS）和 IgG 免疫复合物（IgG IC）诱导的炎症信号通路的激活。通过分子对接和分子动力学模拟阐明了马鞭草苷对 GPR18 激活作用的结构基础。此外，我们确定 IgG IC 通过 CEBP-δ 激活上调 GSDME 和 GSDMD 的表达诱导巨噬细胞焦亡，而马鞭草苷抑制这一过程。此外，我们首次提供了证据表明 IgG IC 促进中性粒细胞胞外诱捕网（NETs）的形成，而马鞭草苷抑制 NETs 的形成。综上所述，我们的研究结果表明马鞭草苷作为一种“植物 resolvin”促进炎症消退，并提示靶向 C/EBP-δ/GSDMD/GSDME 轴抑制巨噬细胞焦亡可能是治疗急性肺损伤和脓毒症的一种新策略。
