Department of Anesthesiology, The People's Hospital of Luoding & Affiliated Luoding Hospital of Guangdong Medical University, Luoding 527200, China.
Department of Anesthesiology, Affiliated Foshan Hospital of SUN YAT-SEN University, Foshan 528000, China.
Biomed Pharmacother. 2018 Oct;106:879-889. doi: 10.1016/j.biopha.2018.07.031. Epub 2018 Jul 11.
Acute kidney injury induced by ischemia-reperfusion injury (IRI) is a high risk factor in the progression towards chronic kidney disease, which is featured by renal interstitial fibrosis. Interleukin (IL)-18 is produced by T cells and macrophages and has been involved in the pathophysiology of IRI. However, the role of IL-18 in IRI-induced renal fibrosis is poorly understood. In the present study, we showed that interleukin (IL)-18 was significantly up-regulated after IRI stress. Mice treated with IL-18 Bp, a natural inhibitor of IL-18, presented less severe fibrotic response in the kidneys following IRI compared with vehicle-treated mice. Inhibition of IL-18 decreased myofibroblasts formation in the kidneys in response to IRI, which was associated with reduction of fibronectin and collagenⅠproteins. Moreover, inhibition of IL-18 impaired infiltration of CD3 T cells and F4/80 macrophages in the kidneys of mice after IRI. Treatment with IL-18 Bp reduces the levels of profibrotic molecules in the kidneys of mice following IRI. Finally, administration of IL-18 Bp impedes the transition of M2 macrophages to myofibroblasts and suppressed the accumulation of bone marrow-derived M2 macrophages. Adoptive transfer of M2 macrophages abolished the anti-fibrotic effect of IL-18 Bp. In summary, our results suggest that IL-18 plays an important role in the progression of IRI-induced renal fibrosis via modulating inflammation cells infiltration, the expression of inflammatory cytokines and chemokines, and the transition of bone marrow-derived M2 macrophages to myofibroblasts.
缺血再灌注损伤（IRI）引起的急性肾损伤是慢性肾脏病进展的高风险因素，其特征为肾间质纤维化。白细胞介素（IL）-18 由 T 细胞和巨噬细胞产生，已参与 IRI 的病理生理学过程。然而，IL-18 在 IRI 诱导的肾纤维化中的作用知之甚少。在本研究中，我们表明，IL-18 在 IRI 应激后显著上调。与 vehicle 治疗的小鼠相比，用 IL-18 Bp（IL-18 的天然抑制剂）治疗的小鼠在 IRI 后肾脏的纤维化反应较轻。IL-18 的抑制作用降低了肾脏中肌成纤维细胞的形成，这与纤维连接蛋白和胶原Ⅰ蛋白的减少有关。此外，IL-18 的抑制作用损害了 IRI 后小鼠肾脏中 CD3 T 细胞和 F4/80 巨噬细胞的浸润。用 IL-18 Bp 治疗可降低 IRI 后小鼠肾脏中促纤维化分子的水平。最后，IL-18 Bp 的给药阻碍了 M2 巨噬细胞向肌成纤维细胞的转化，并抑制了骨髓源性 M2 巨噬细胞的积累。M2 巨噬细胞的过继转移消除了 IL-18 Bp 的抗纤维化作用。总之，我们的结果表明，IL-18 通过调节炎症细胞浸润、炎症细胞因子和趋化因子的表达以及骨髓源性 M2 巨噬细胞向肌成纤维细胞的转化，在 IRI 诱导的肾纤维化进展中发挥重要作用。
