image: EGR1high is present in IgG4-RD patients and contributes substantially to tissue fibrosis via EMT and direct activation of fibroblasts. Immune-epithelial interaction is an important driver of overexpression of EGR1 in epithelial cells.
Credit: ©Science China Press
IgG4-RD is a chronic immune-mediated inflammatory disorder characterized by multi-organ swelling and sclerosis, massive infiltration of lymphocytes and plasma cells in affected tissues, and prominent fibrosis. It can involve crucial organs such as the pancreas, lacrimal glands, salivary glands, retroperitoneum, lungs, and kidneys, and often relapses with conventional treatments. Previous research primarily focused on immune cell abnormalities. In contrast, this study innovatively analyzed single-cell RNA sequencing data from IgG4-RD patients and conducted cell model experiments, shifting the focus to a previously overlooked player – the epithelial cells within the lesioned tissues.
The study found that EGR1 expression levels in epithelial cells from affected tissues of IgG4-RD patients were significantly higher than in normal tissues. More importantly, these EGR1-high epithelial cells exhibited distinct features of epithelial-mesenchymal transition (EMT): a transformation in cell morphology and function towards mesenchymal cells, accompanied by a reduction in the epithelial cell marker E-cadherin (E-cad) and a significant increase in mesenchymal/fibrosis markers including vimentin (VIM), fibronectin (FN1), and α-smooth muscle actin (α-SMA). This transformation process directly enhanced the migratory capacity of epithelial cells, serving as a critical starting point for abnormal tissue remodeling.
To further investigate the role of EGR1, the researchers constructed EGR1 overexpression (OE-EGR1) and knockdown (si-EGR1) models using submandibular gland (A253) and pancreatic (HPNE) epithelial cells. Experimental results showed that EGR1 overexpression successfully induced the expression of mesenchymal and fibrosis markers like VIM, FN1, and α-SMA in these epithelial cells and significantly enhanced their migratory ability. Furthermore, the culture supernatant derived from EGR1-high epithelial cells was found to effectively promote the proliferation and migration of fibroblasts and upregulate the expression of their fibrosis-related markers. This is the first time a crucial mechanism has been revealed: lesioned epithelial cells activate fibroblasts – the primary effector cells of fibrosis – through the secretion of specific factors.
Through co-culture experiments, the study further elucidated that cytokines released by activated CD14⁺ monocytes and M2-type macrophages differentiated from them in the disease environment can upregulate EGR1 expression in epithelial cells, thereby inducing EMT. This delineates a clear pathogenic network: "Immune cells → Epithelial cells (EGR1↑/EMT) → Fibroblast activation → Tissue fibrosis", with EGR1 acting as the central signaling hub within this network.
Professor Wen Zhang and Associate Researcher Xunyao Wu from the Chinese Academy of Medical Sciences & Peking Union Medical College Hospital are the co-corresponding authors of the article. Ph.D. candidates Ruijie Sun and Qinhuan Luo from Peking Union Medical College are the co-first authors. This research was supported by projects including the National Key Research and Development Program of the 14th Five-Year Plan and the National Natural Science Foundation of China.
See the article:
Epithelial cells facilitate tissue fibrosis through early growth response-1 overexpression in IgG4-related disease
Journal
Science Bulletin