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Updated: Jan 16, 2026
Mouse Models of Epididymitis Induced by Pathogen-Associated Molecular Patterns
Published on: December 12, 2025
Macrophage transition to a myofibroblast state drives fibrotic disease in uropathogenic E. coli-induced
Ming Wang1, Xu Chu2, Zhongyu Fan3
1Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Abstract:
Bacterial infections, particularly uropathogenic E. coli (UPEC), contribute substantially to male infertility through tissue damage and subsequent fibrosis in the testis and epididymis. The role of testicular macrophages (TMs), a diverse cell population integral to tissue maintenance and immune balance, in fibrosis is not fully understood. Here, we used single-cell RNA sequencing in a murine model of epididymo-orchitis to analyze TM dynamics during UPEC infection. Our study identified a marked increase in S100a4+ macrophages, originating from monocytes, strongly associated with fibrotic changes. This association was validated in human testicular and epididymal samples. We further demonstrated that S100a4+ macrophages transition to a myofibroblast-like phenotype, producing extracellular matrix proteins such as collagen I and fibronectin. S100a4, both extracellular and intracellular, activated collagen synthesis through the TGF-β/STAT3 signaling pathway, highlighting this pathway as a therapeutic target. Inhibition of S100a4 with niclosamide or macrophage-specific S100a4 KO markedly reduced immune infiltration, tissue damage, and fibrosis in infected murine models. Our findings establish the critical role of S100a4+ macrophages in fibrosis during UPEC-induced epididymo-orchitis and propose them as potential targets for antifibrotic therapy development.
Insights
Uropathogenic E. coli infections cause male infertility via testicular fibrosis. S100a4+ macrophages drive this fibrosis by promoting collagen production, offering a new therapeutic target for male infertility.
Area of Science:
- Reproductive immunology
- Cell biology
- Pathology
Background:
- Bacterial infections, like uropathogenic E. coli (UPEC), are a significant cause of male infertility.
- Testicular fibrosis, resulting from infection-induced tissue damage in the testis and epididymis, contributes to infertility.
- The specific role of testicular macrophages (TMs) in mediating fibrosis during infection remains unclear.
Purpose of the Study:
- To investigate the dynamics of testicular macrophages during UPEC infection.
- To elucidate the role of specific macrophage populations in driving testicular fibrosis.
- To identify potential therapeutic targets for mitigating infection-induced male infertility.
Main Methods:
- Single-cell RNA sequencing was employed in a murine model of epididymo-orchitis.
- Macrophage populations and their gene expression profiles were analyzed during UPEC infection.
- The function of S100a4+ macrophages and the TGF-β/STAT3 pathway was investigated.
- Therapeutic interventions targeting S100a4 were tested in vivo.
Main Results:
- A significant increase in S100a4+ macrophages, derived from monocytes, was observed and correlated with fibrotic changes in murine and human samples.
- S100a4+ macrophages adopted a myofibroblast-like phenotype, producing extracellular matrix proteins like collagen I and fibronectin.
- S100a4 activated collagen synthesis via the TGF-β/STAT3 pathway.
- Inhibition of S100a4 reduced immune infiltration, tissue damage, and fibrosis.
Conclusions:
- S100a4+ macrophages play a critical role in promoting fibrosis during UPEC-induced epididymo-orchitis.
- The TGF-β/STAT3 signaling pathway is implicated in S100a4-mediated fibrosis.
- Targeting S100a4 presents a promising therapeutic strategy for antifibrotic treatment in male infertility.
