Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Department of Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Exp Eye Res. 2021 Jul;208:108627. doi: 10.1016/j.exer.2021.108627. Epub 2021 May 25.
Corneal transplantation rejection remains a major threat to the success rate of high-risk patients. Given the many side effects presented by traditional immunosuppressants, there is an urgency to clarify the mechanism of corneal transplantation rejection and to identify new therapeutic targets. Kaempferol is a natural flavonoid that has been proven in various studies to possess anti-inflammatory, antioxidant, anticancer, and neuroprotective properties. However, the effect of Ka on corneal transplantation remains largely unexplored. To address this, both at the in vivo and in vitro levels, we established a model of corneal allograft transplantation in Wistar rats and an LPS-induced inflammatory model using human THP-1-derived macrophages. In the transplantation experiments, we observed an enhancement of mRNA and protein level in the NLRP3/IL-1 β axis and in M1 macrophage polarization post-operation. In groups to which kaempferol intraperitoneal injections were administered, this response was effectively reduced. However, the effect of kaempferol was reversed after the application of autophagy inhibitors. Similarly, in the inflammatory model, we found that different concentrations of kaempferol reduced the LPS-induced M1 polarization and NLRP3 inflammasome activation. Moreover, we confirmed that kaempferol induced autophagy and that autophagy inhibitors reversed this effect in macrophages. In conclusion, we found that kaempferol can inhibit the activation of NLRP3 inflammasomes by inducing autophagy, thus inhibiting macrophage polarization, and ultimately alleviating corneal transplantation rejection. Thus, our study suggests that kaempferol is a potential therapeutic agent in the treatment of allograft rejection.
角膜移植排斥仍然是高危患者成功率的主要威胁。鉴于传统免疫抑制剂存在许多副作用，迫切需要阐明角膜移植排斥的机制，并确定新的治疗靶点。山奈酚是一种天然类黄酮，多项研究已经证明其具有抗炎、抗氧化、抗癌和神经保护作用。然而，山奈酚对角膜移植的影响在很大程度上仍未得到探索。为了解决这个问题，我们在体内和体外水平都建立了 Wistar 大鼠角膜同种异体移植模型和人 THP-1 衍生巨噬细胞 LPS 诱导的炎症模型。在移植实验中，我们观察到术后 NLRP3/IL-1β 轴和 M1 巨噬细胞极化的 mRNA 和蛋白水平增强。在给予山奈酚腹腔注射的组中，这种反应得到了有效抑制。然而，在用自噬抑制剂处理后，山奈酚的作用被逆转。同样，在炎症模型中，我们发现不同浓度的山奈酚可降低 LPS 诱导的 M1 极化和 NLRP3 炎性小体激活。此外，我们证实山奈酚诱导自噬，而自噬抑制剂逆转了巨噬细胞中的这种作用。总之，我们发现山奈酚可以通过诱导自噬抑制 NLRP3 炎性小体的激活，从而抑制巨噬细胞极化，最终缓解角膜移植排斥。因此，我们的研究表明山奈酚是治疗同种异体排斥反应的一种潜在治疗药物。
