Isot Ibrahim, Kim Seong Hoon, Demirel-Yalciner Tugce, Migni Anna, Gioiello Antimo, Galli Francesco, Sozen Erdi, Surh Young-Joon, Ozer Nesrin Kartal
Department of Biochemistry, Faculty of Medicine, Marmara University, Istanbul, Türkiye; Institute of Health Sciences, Marmara University, Istanbul, Türkiye.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.
Free Radic Biol Med. 2025 May 29;237:37-45. doi: 10.1016/j.freeradbiomed.2025.05.428.
Inflammation resolution represents the most crucial step in the inflammatory response, and its disruption is associated with a variety of disorders. Clearance of apoptotic cells, namely efferocytosis, plays a pivotal role in this process by preventing the transition of apoptotic cell accumulation into necrosis and fibrosis. Garcinoic acid (GA), a plant metabolite and a postbiotics analogue of vitamin E, has been demonstrated to possess anti-inflammatory activity, but mechanistic aspects of this effect remain poorly characterized. In this study, we explored the potential of GA in enhancing efferocytosis and inflammation resolution. In vitro findings using macrophages indicated that GA enhances efferocytosis through the involvement of MerTK, LRP-1, and TIM4, and specialized pro-resolving lipid mediators (SPMs), mainly lipoxin A4 and resolvin E1. As in vivo, GA reduced inflammatory and degenerative symptoms in a mouse model of dextran sodium sulfate (DSS)-induced colitis, which was associated with increased efferocytosis activity in colon. Mechanistically, Nrf2 silencing and HO-1 inhibition in macrophages reduced both efferocytosis and SPMs effects of GA, suggesting that the pro-resolving role of this metabolite may depend, at least partially, on Nrf2 activity and stress response effects. Present findings demonstrate a role of GA as efferocytosis enhancer and potential therapeutic agent in non-resolving diseases.
炎症消退是炎症反应中最关键的步骤，其破坏与多种疾病相关。凋亡细胞的清除，即胞葬作用，通过防止凋亡细胞积累转变为坏死和纤维化，在这一过程中发挥着关键作用。 Garcinoic酸（GA）是一种植物代谢产物，也是维生素E的后生元类似物，已被证明具有抗炎活性，但其作用机制仍不清楚。在本研究中，我们探讨了GA在增强胞葬作用和炎症消退方面的潜力。使用巨噬细胞的体外研究结果表明，GA通过MerTK、LRP-1和TIM4以及主要是脂氧素A4和消退素E1的特异性促消退脂质介质（SPM）来增强胞葬作用。在体内，GA减轻了葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型中的炎症和退行性症状，这与结肠中胞葬作用活性增加有关。从机制上讲，巨噬细胞中的Nrf2沉默和HO-1抑制降低了GA的胞葬作用和SPM效应，表明这种代谢产物的促消退作用可能至少部分取决于Nrf2活性和应激反应效应。目前的研究结果表明GA作为胞葬作用增强剂和在非消退性疾病中的潜在治疗剂的作用。
