巨噬细胞移动抑制因子通过促进成纤维细胞中磷脂代谢产物前列腺素E2的产生来介导关节囊纤维化。

Macrophage migration inhibitory factor mediates joint capsule fibrosis via facilitating phospholipid metabolite PGE2 production in fibroblasts.

作者信息

Zhang Yuxin, Jiao Xin, Wang Yijia, Liu Shilu, Wang Zengguang, Chang Hanwen, Li Yuntao, Yue Xiaokun, Gu Xiaoding, Xu Renjie

机构信息

Department of Rehabilitation Medicine, Shanghai Second People's Hospital, 200011, Shanghai, China.

Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China.

出版信息

Cell Mol Life Sci. 2025 Jul 19;82(1):279. doi: 10.1007/s00018-025-05800-y.

DOI:10.1007/s00018-025-05800-y

PMID:40682591

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12276190/

Abstract

BACKGROUND

Joint capsule persistent inflammation and subsequent fibrosis lead to post-traumatic joint contracture (PTJC). Fibroblasts, as a bridge between inflammation and fibrosis, participate in regulating the pathological microenvironment after injury. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that can be inducibly expressed in lesioned joint capsule, yet its role in regulating fibroblast function to tune milieu following PTJC remains elusive.

METHODS

The influence of MIF on the expression of phospholipid metabolite prostaglandin E2 (PGE2) and relevant pathways were investigated using qRT-PCR, Western blot, ELISA, EdU, Transwell, siRNA, and immunofluorescence following establishment of rat PTJC model, fibroblast model, and macrophage model.

RESULTS

MIF/COX2/PGE2 synchronously increased in injured joint capsules following PTJC. Treatment the lesion sites with MIF inhibitor 4-IPP significantly reduced the expression of COX2 and PGE2. In vitro, MIF activated COX2/PGE2 pathway in joint capsule fibroblasts through interaction with membrane receptor CD74 and subsequent regulation of ERK/CREB signaling. Joint capsule fibroblast-derived PGE2 in turn selectively modulated fibroblast and macrophage functions to synergistically promote the inflammation and fibrosis process.

CONCLUSIONS

Our results reveal a novel function of MIF-mediated fibroblast, which tunes pathological microenvironment by activating phospholipid metabolism to accelerate and exacerbate joint capsule inflammation and fibrosis. These suggest a new insights and potential therapeutic strategy for inflammation- and fibrosis-associated diseases.

摘要

背景

关节囊持续性炎症及随后的纤维化导致创伤后关节挛缩（PTJC）。成纤维细胞作为炎症与纤维化之间的桥梁，参与损伤后病理微环境的调节。巨噬细胞移动抑制因子（MIF）是一种促炎细胞因子，可在损伤的关节囊中诱导表达，但其在PTJC后调节成纤维细胞功能以调节微环境中的作用仍不清楚。

方法

在建立大鼠PTJC模型、成纤维细胞模型和巨噬细胞模型后，使用qRT-PCR、蛋白质免疫印迹法、酶联免疫吸附测定、EdU、Transwell、小干扰RNA和免疫荧光法研究MIF对磷脂代谢产物前列腺素E2（PGE2）表达及相关通路的影响。

结果

PTJC后损伤关节囊中MIF/COX2/PGE2同步增加。用MIF抑制剂4-IPP处理损伤部位可显著降低COX2和PGE2的表达。在体外，MIF通过与膜受体CD74相互作用并随后调节ERK/CREB信号传导，激活关节囊成纤维细胞中的COX2/PGE2通路。关节囊成纤维细胞衍生的PGE2反过来选择性调节成纤维细胞和巨噬细胞功能，协同促进炎症和纤维化过程。