Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis
Involvement of PARK2-Mediated Mitophagy in Idiopathic Pulmonary Fibrosis Pathogenesis
复制标题
DOI：
10.4049/jimmunol.1600265
复制
发表时间：
2016-07-15
影响因子：
4.4
通讯作者：
Kuwano, Kazuyoshi
中科院分区：
文献类型：
--
作者：
Kobayashi, Kenji;Araya, Jun;Kuwano, Kazuyoshi
成纤维细胞灶是特发性肺纤维化（IPF）纤维化发展的前沿，由纤维化肌成纤维细胞组成。自噬参与肌成纤维细胞分化的调节。线粒体自噬（线粒体选择性自噬）不足会导致活性氧增加，这可能会调节肌成纤维细胞分化的细胞信号传导途径。因此，我们试图研究线粒体自噬在肌成纤维细胞分化中的调节作用，作为 IPF 发病机制的一部分。肺成纤维细胞用于体外实验。对 IPF 肺组织进行免疫组织化学评估。研究人员将 PARK2 作为线粒体自噬调节的靶分子进行了检查，并在博来霉素诱导的肺纤维化模型中采用了 PARK2 敲除小鼠。我们证明，PARK2 敲低介导的线粒体自噬抑制参与了血小板源性生长因子受体 (PDGFR)/PI3K/AKT 信号通路的激活机制，同时增强了肌成纤维细胞的分化和增殖，而抗氧化剂和 PDGFR 抑制剂 AG1296 明显抑制了肌成纤维细胞的分化和增殖。线粒体自噬抑制介导的 PDGFR 信号传导激活导致进一步的自噬抑制，表明线粒体自噬抑制和 PDGFR 激活的自我放大循环的存在。 IPF 肺显示 PARK2 减少，同时 PDGFR 磷酸化增加。此外，博来霉素诱导的肺纤维化在 PARK2 敲除小鼠中得到增强，随后被 AG1296 抑制。这些发现表明，线粒体自噬介导的 PDGFR/PI3K/AKT 激活不足（主要归因于 PARK2 表达减少）是 IPF 发病过程中成纤维细胞灶形成中肌成纤维细胞分化和增殖的潜在机制。
Fibroblastic foci, known to be the leading edge of fibrosis development in idiopathic pulmonary fibrosis (IPF), are composed of fibrogenic myofibroblasts. Autophagy has been implicated in the regulation of myofibroblast differentiation. Insufficient mitophagy, the mitochondria-selective autophagy, results in increased reactive oxygen species, which may modulate cell signaling pathways for myofibroblast differentiation. Therefore, we sought to investigate the regulatory role of mitophagy in myofibroblast differentiation as a part of IPF pathogenesis. Lung fibroblasts were used in in vitro experiments. Immunohistochemical evaluation in IPF lung tissues was performed. PARK2 was examined as a target molecule for mitophagy regulation, and a PARK2 knockout mouse was employed in a bleomycin-induced lung fibrosis model. We demonstrated that PARK2 knockdown-mediated mitophagy inhibition was involved in the mechanism for activation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT signaling pathway accompanied by enhanced myofibroblast differentiation and proliferation, which were clearly inhibited by treatment with both antioxidants and AG1296, a PDGFR inhibitor. Mitophagy inhibition-mediated activation of PDGFR signaling was responsible for further autophagy suppression, suggesting the existence of a self-amplifying loop of mitophagy inhibition and PDGFR activation. IPF lung demonstrated reduced PARK2 with concomitantly increased PDGFR phosphorylation. Furthermore, bleomycin-induced lung fibrosis was enhanced in PARK2 knockout mice and subsequently inhibited by AG1296. These findings suggest that insufficient mitophagy-mediated PDGFR/PI3K/AKT activation, which is mainly attributed to reduced PARK2 expression, is a potent underlying mechanism for myofibroblast differentiation and proliferation in fibroblastic foci formation during IPF pathogenesis.