自噬抑制在胎儿来源胎盘间充质干细胞的 IL-1β 微环境下恢复 CD200 的表达，并提高其治疗肺纤维化的潜力。

Autophagy inhibition restores CD200 expression under IL-1β microenvironment in placental mesenchymal stem cells of fetal origin and improves its pulmonary fibrosis therapeutic potential.

机构信息

School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China.

The Center of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China.

出版信息

Mol Immunol. 2022 Nov;151:29-40. doi: 10.1016/j.molimm.2022.08.014. Epub 2022 Sep 6.

DOI:10.1016/j.molimm.2022.08.014

PMID:36075140

Abstract

BACKGROUND

Mesenchymal stem cells (MSCs) are promising remedies for various inflammatory disease including pulmonary fibrosis (PF). However, the properties of MSCs in PF pathological microenvironment remain unclear. In this study, the efficacy of autophagy in placental mesenchymal stem cells of fetal origin (fPMSCs) in either IL-1β treatment or BLM induced pulmonary fibrosis mice model was examined.

METHODS

The characteristic of fPMSCs was identified by morphological observation, flow cytometry and differentiation potential. In vitro experiments, fPMSCs were stimulated with IL-1β, to mimic inflammatory microenvironment of pulmonary fibrosis. The immunosuppressive properties and autophagic function in fPMSCs treated with IL-1β were evaluated by both macrophage cells THP-1 activation and the expression of CD200 situation, autophagy marker and MAPK signaling pathway. The in vivo anti-fibrotic activity of fPMSCs interfering autophagy was evaluated by using BLM induced pulmonary fibrosis mice model.

RESULTS

fPMSCs belonged to CD73CD90CD105/CD14 CD34CD45HLA-DR cells, and capable differentiation to adipogenic, osteogenic and chondrogenic cells. In addition, immunoinhibitory activity of fPMSCs for macrophage was restrained by IL-1β treatment in CD200 dependent manner. Suppression of autophagy by sh-Atg5 lentivirus increased the expression of CD200 and ratio of CD200 positive fPMSCs, and enhanced fPMSCs immunosuppression for THP-1 activation. Mechanistically, IL-1β induced autophagy regulated by p38 signaling cascade. In vivo, autophagy inhibition induced by Atg5 knockdown in fPMSCs resulted in strengthening antifibrotic effects on PF mice model.

CONCLUSIONS

Collectively, autophagy derived from inflammatory microenvironment hampered the immunoinhibitory properties of MSCs. Based on this, adjustment of autophagy may be a valid approach to facilitate their immunomodulatory and anti-fibrotic efficacy.

摘要

背景

间充质干细胞（MSCs）是治疗各种炎症性疾病的有前途的方法，包括肺纤维化（PF）。然而，MSCs 在 PF 病理微环境中的特性尚不清楚。在这项研究中，我们研究了源自胎盘的间充质干细胞（fPMSCs）中的自噬在白细胞介素-1β（IL-1β）处理或博来霉素（BLM）诱导的肺纤维化小鼠模型中的功效。

方法

通过形态观察、流式细胞术和分化潜能鉴定 fPMSCs 的特征。在体外实验中，用 IL-1β 刺激 fPMSCs，以模拟肺纤维化的炎症微环境。通过 THP-1 激活和 CD200 表达情况评估 fPMSCs 经 IL-1β 处理后的免疫抑制特性和自噬功能，自噬标志物和 MAPK 信号通路。通过 BLM 诱导的肺纤维化小鼠模型评估干扰自噬的 fPMSCs 的体内抗纤维化活性。

结果

fPMSCs 属于 CD73+CD90+CD105/CD14-CD34-CD45-HLA-DR 细胞，能够向成脂、成骨和成软骨细胞分化。此外，IL-1β 处理以 CD200 依赖的方式抑制 fPMSCs 对巨噬细胞的免疫抑制活性。sh-Atg5 慢病毒抑制自噬增加了 CD200 的表达和 CD200 阳性 fPMSCs 的比例，并增强了 fPMSCs 对 THP-1 激活的免疫抑制作用。在机制上，IL-1β 诱导的自噬受 p38 信号级联调节。在体内，fPMSCs 中 Atg5 敲低诱导的自噬抑制导致 PF 小鼠模型的抗纤维化作用增强。