Department of Nephrology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
Front Immunol. 2019 Apr 30;10:784. doi: 10.3389/fimmu.2019.00784. eCollection 2019.
Fractalkine (FKN), also known as chemokine (C-X3-C motif) ligand 1, constitutes an intriguing chemokine with a documented role in the development of numerous inflammatory diseases including autoimmune disease. Specifically, it has been reported that FKN is involved in the disease progression of lupus nephritis (LN). The epithelial-mesenchymal transition (EMT) plays a significant role in the formation of tubulointerstitial lesions (TIL), which are increasingly recognized as a hallmark of tissue fibrogenesis after injury. However, the correlation between FKN and EMT or TIL in LN has not been determined. To investigate the potential role of FKN in EMT and TIL, MRL lymphoproliferation (MRL/lpr) strain mice were treated with an anti-FKN antibody, recombinant-FKN chemokine domain, or isotype antibody. Our results revealed that treatment with the anti-FKN antibody improved EMT, TIL, and renal function in MRL/lpr mice, along with inhibiting activation of the Wnt/β-catenin signaling pathway. In contrast, administration of the recombinant-FKN chemokine domain had the opposite effect. Furthermore, to further explore the roles of FKN in EMT, we assessed the levels of EMT markers in FKN-depleted or overexpressing human proximal tubule epithelial HK-2 cells. Our results provide the first evidence that the E-cadherin level was upregulated, whereas α-SMA and vimentin expression was downregulated in FKN-depleted HK-2 cells. In contrast, overexpression of FKN in HK-2 cells enhanced EMT. In addition, inhibition of the Wnt/β-catenin pathway by XAV939 negated the effect of FKN overexpression, whereas activation of the Wnt/β-catenin pathway by Ang II impaired the effect of the FKN knockout on EMT in HK-2 cells. Together, our data indicate that FKN plays essential roles in the EMT progression and development of TIL in MRL/lpr mice, most likely through activation of the Wnt/β-catenin signaling pathway.
趋化因子（C-X3-C 基序）配体 1（也称为 fractalkine，FKN）是一种具有独特作用的趋化因子，在多种炎症性疾病的发生和发展中发挥着重要作用，包括自身免疫性疾病。具体而言，已有研究表明 FKN 参与了狼疮肾炎（LN）的疾病进展。上皮间质转化（EMT）在肾小管间质损伤（TIL）的形成中起着重要作用，TIL 被越来越多地认为是损伤后组织纤维化的一个标志。然而，FKN 与 LN 中的 EMT 或 TIL 之间的相关性尚未确定。为了研究 FKN 在 EMT 和 TIL 中的潜在作用，我们使用抗 FKN 抗体、重组 FKN 趋化因子结构域或同型抗体对 MRL 淋巴增生（MRL/lpr）品系小鼠进行了处理。我们的研究结果表明，用抗 FKN 抗体治疗可改善 MRL/lpr 小鼠的 EMT、TIL 和肾功能，并抑制 Wnt/β-catenin 信号通路的激活。相反，给予重组 FKN 趋化因子结构域则产生相反的效果。此外，为了进一步探讨 FKN 在 EMT 中的作用，我们评估了 FKN 耗尽或过表达的人近端肾小管上皮细胞 HK-2 中 EMT 标志物的水平。我们的研究结果首次表明，FKN 耗尽可上调 E-钙黏蛋白水平，而下调 α-SMA 和波形蛋白的表达。相反，在 HK-2 细胞中过表达 FKN 可增强 EMT。此外，XAV939 抑制 Wnt/β-catenin 通路可消除 FKN 过表达的作用，而 Ang II 激活 Wnt/β-catenin 通路则可削弱 FKN 敲除对 HK-2 细胞 EMT 的影响。综上所述，我们的数据表明，FKN 在 MRL/lpr 小鼠 EMT 进展和 TIL 形成中发挥着重要作用，这可能是通过激活 Wnt/β-catenin 信号通路实现的。
