Department of Nephrology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
Science laboratory, Youjiang Medical University for Nationalities, Baise, China.
J Cell Mol Med. 2021 Jul;25(14):6963-6975. doi: 10.1111/jcmm.16707. Epub 2021 Jun 7.
Fractalkine (CX3CL1, FKN), a CX3C gene sequence inflammatory chemokine, has been found to have pro-inflammatory and pro-adhesion effects. Macrophages are immune cells with a critical role in regulating the inflammatory response. The imbalance of M1/M2 macrophage polarization can lead to aggravated inflammation. This study attempts to investigate the mechanisms through which FKN regulates macrophage activation and the acute kidney injury (AKI) involved in inflammatory response induced by lipopolysaccharide (LPS) by using FKN knockout (FKN-KO) mice and cultured macrophages. It was found that FKN and Wnt/β-catenin signalling have a positive interaction in macrophages. FKN overexpression inhibited LPS-induced macrophage apoptosis. However, it enhanced their cell viability and transformed them into the M2 type. The effects of FKN overexpression were accelerated by activation of Wnt/β-catenin signalling. In the in vivo experiments, FKN deficiency suppressed macrophage activation and reduced AKI induced by LPS. Inhibition of Wnt/β-catenin signalling and FKN deficiency further mitigated the pathologic process of AKI. In summary, we provide a novel mechanism underlying activation of macrophages in LPS-induced AKI. Although LPS-induced murine AKI was unable to completely recapitulate human AKI, the positive interactions between FKN and Wnt/β-catenin signalling pathway may be a therapeutic target in the treatment of kidney injury.
趋化因子（CX3CL1，FKN）是一种 CX3C 基因序列炎症趋化因子，具有促炎和促黏附作用。巨噬细胞是一种具有调节炎症反应关键作用的免疫细胞。M1/M2 巨噬细胞极化失衡可导致炎症加重。本研究试图通过使用 FKN 敲除（FKN-KO）小鼠和培养的巨噬细胞，研究 FKN 调节巨噬细胞激活和脂多糖（LPS）诱导的炎症反应中急性肾损伤（AKI）的机制。结果发现，FKN 和 Wnt/β-catenin 信号在巨噬细胞中有正相互作用。FKN 过表达抑制 LPS 诱导的巨噬细胞凋亡，但增强了其细胞活力并将其转化为 M2 型。Wnt/β-catenin 信号的激活加速了 FKN 过表达的作用。在体内实验中，FKN 缺乏抑制了 LPS 诱导的巨噬细胞激活并减轻了 LPS 诱导的 AKI。Wnt/β-catenin 信号通路的抑制和 FKN 缺乏进一步减轻了 AKI 的病理过程。总之，我们为 LPS 诱导的 AKI 中巨噬细胞激活提供了一个新的机制。虽然 LPS 诱导的小鼠 AKI 无法完全重现人类 AKI，但 FKN 和 Wnt/β-catenin 信号通路之间的正相互作用可能是治疗肾脏损伤的一个治疗靶点。
