Fibrosis, vascular activation, and immune abnormalities resembling systemic sclerosis in bleomycin-treated Fli-1-haploinsufficient mice.
Fibrosis, vascular activation, and immune abnormalities resembling systemic sclerosis in bleomycin-treated Fli-1-haploinsufficient mice.
复制标题
DOI：
10.1002/art.38948
复制
发表时间：
2015-02
影响因子：
13.3
通讯作者：
Sato, Shinichi
中科院分区：
文献类型：
--
作者：
Taniguchi, Takashi;Asano, Yoshihide;Akamata, Kaname;Noda, Shinji;Takahashi, Takehiro;Ichimura, Yohei;Toyama, Tetsuo;Trojanowska, Maria;Sato, Shinichi
Fli-1 是系统性硬化症 (SSc) 的潜在诱发因素，通过表观遗传机制在 SSc 患者的病变皮肤中持续下调。为了研究 Fli-1 缺陷对各种细胞类型中 SSc 表型诱导的影响，我们在 Fli-1+/- 小鼠中产生了博来霉素诱导的皮肤纤维化，并研究了其表型改变背后的分子机制。通过定量逆转录聚合酶链反应和免疫染色检查靶分子的信使 RNA (mRNA) 水平和蛋白质表达。转化生长因子β（TGFβ）生物测定用于评估潜在TGFβ的激活。通过染色质免疫沉淀评估 Fli-1 与靶基因启动子的结合。博来霉素在 Fli-1+/- 小鼠中诱导比野生型小鼠更严重的真皮纤维化。 Fli-1 单倍体不足通过 αvβ3 和 αvβ5 整合素的上调以及潜在 TGFβ 的激活来激活真皮成纤维细胞。 Fli-1+/- 小鼠的真皮纤维化也可归因于内皮细胞向间质细胞的转变，这种转变是由 Fli-1 缺陷直接诱导的，并由博来霉素放大。 Th2/Th17 偏向炎症以及肥大细胞和巨噬细胞浸润增加，部分原因是内皮细胞中细胞粘附分子表达的改变以及皮肤趋化因子的诱导。 Fli-1+/- 小鼠巨噬细胞在白介素 4 (IL-4) 或 IL-13 刺激下优先分化为 M2 表型。我们的研究结果为 Fli-1 缺陷在以与人类疾病一致的方式诱导真皮成纤维细胞、内皮细胞和巨噬细胞中 SSc 样表型改变中的基本作用提供了有力的证据。
Fli-1, a potential predisposing factor for systemic sclerosis (SSc), is constitutively down-regulated in the lesional skin of patients with SSc by an epigenetic mechanism. To investigate the impact of Fli-1 deficiency on the induction of an SSc phenotype in various cell types, we generated bleomycin-induced skin fibrosis in Fli-1+/− mice and investigated the molecular mechanisms underlying its phenotypic alterations. Messenger RNA (mRNA) levels and protein expression of target molecules were examined by quantitative reverse transcription–polymerase chain reaction and immunostaining. Transforming growth factor β (TGFβ) bioassay was used to evaluate the activation of latent TGFβ. The binding of Fli-1 to the target gene promoters was assessed with chromatin immunoprecipitation. Bleomycin induced more severe dermal fibrosis in Fli-1+/− mice than in wild-type mice. Fli-1 haploinsufficiency activated dermal fibroblasts via the up-regulation of αvβ3 and αvβ5 integrins and activation of latent TGFβ. Dermal fibrosis in Fli-1+/− mice was also attributable to endothelial-to-mesenchymal transition, which is directly induced by Fli-1 deficiency and amplified by bleomycin. Th2/Th17-skewed inflammation and increased infiltration of mast cells and macrophages were seen, partly due to the altered expression of cell adhesion molecules in endothelial cells as well as the induction of the skin chemokines. Fli-1+/− mouse macrophages preferentially differentiated into an M2 phenotype upon stimulation with interleukin-4 (IL-4) or IL-13. Our findings provide strong evidence for the fundamental role of Fli-1 deficiency in inducing SSc-like phenotypic alterations in dermal fibroblasts, endothelial cells, and macrophages in a manner consistent with human disease.
登录
查看更多内容
影响因子：
2.9
作者：
ABE, M;HARPEL, JG;RIFKIN, DB
通讯作者：
RIFKIN, DB
影响因子：
5.4
作者：
Bujor AM;Haines P;Padilla C;Christmann RB;Junie M;Sampaio-Barros PD;Lafyatis R;Trojanowska M
通讯作者：
Trojanowska M
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
15.9
作者：
Asano, Y;Ihn, H;Tamaki, K
通讯作者：
Tamaki, K
影响因子：
6
作者：
Kubo, M;Czuwara-Ladykowska, J;Trojanowska, M
通讯作者：
Trojanowska, M