Macrophage-derived IL-1β drives endothelial-mesenchymal transition in diabetes mellitus erectile dysfunction
4 affiliations
- 1Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080 China
- 2Department of Andrology, Center for Men’s Health, Shanghai General Hospital, Urologic Medical Center, Shanghai Jiao Tong University School of Medicine, No.85 Wujin Road, Hongkou District, Shanghai, 200080 China
- 3Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266011 China
- 4Department of Urology, School of Medicine, Shanghai Children’s Hospital, Shanghai Jiao T ong University, Shanghai, 200062 China
Abstract
Background: Diabetes mellitus erectile dysfunction (DMED) is frequently accompanied by corpus cavernosum (CC) fibrosis and endothelial dysfunction; however, the cellular drivers and molecular mechanisms underlying these pathological changes remain incompletely understood. Endothelial-to-mesenchymal transition (EndMT), a phenotypic conversion in which endothelial cells lose endothelial characteristics and acquire mesenchymal features, has emerged as a key contributor to tissue fibrosis under inflammatory and metabolic stress conditions. Macrophages (Mφ), the predominant immune cell population in CC tissue in diabetes, are major sources of pro-inflammatory cytokines and may promote fibrosis by driving EndMT. This study investigated the role and mechanisms of Mφ in CC fibrosis during DMED and explored potential therapeutic targets.
Results: In a streptozotocin-induced DMED rat model, erectile function was significantly impaired, as evidenced by a marked reduction in the maximum intracavernous pressure-to-mean arterial pressure (ICP-to-MAP) ratio. This functional deterioration resulted from pronounced Mφ infiltration and enhanced fibrotic remodeling in CC. Pharmacological depletion of Mφ using clodronate liposomes significantly restored erectile function and increased the smooth muscle-to-collagen ratio. In vitro, co-culture of corpus cavernosum endothelial cells (CCEC) with Mφ under high-glucose (HG) conditions impaired endothelial tube formation and sprouting capacity, accelerated wound closure, and induced EndMT, characterized by downregulation of endothelial markers (CD34 and VE-cadherin) and upregulation of mesenchymal markers (Vimentin and α-SMA). RNA sequencing identified enrichment of interleukin-1 (IL-1)–related responses and Nuclear factor kappa B (NF-κB) signaling during EndMT. Further analyses demonstrated that HG stimulated Mφ to upregulate and secrete interleukin-1 beta (IL-1β), which in turn induced EndMT in CCEC accompanied by activation of NF-κB signaling, as evidenced by increased phosphorylation of p65 and IκBα. Pharmacological inhibition of the IL-1 receptor or NF-κB signaling effectively attenuated EndMT in vitro. Notably, in vivo administration of the IL-1 receptor antagonist Anakinra significantly improved erectile function and suppressed EndMT-associated molecular changes in DMED rats.
Conclusions: Mφ-derived IL-1β promotes cavernosal fibrosis and erectile dysfunction in diabetes by inducing EndMT through activation of the NF-κB pathway. Targeting the IL-1β/NF-κB/EndMT axis represents a promising therapeutic strategy for the treatment of DMED.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13578-026-01627-7.
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BibTeX
@article{zhang2026macrophagederived,
title = {{Macrophage-derived IL-1β drives endothelial-mesenchymal transition in diabetes mellitus erectile dysfunction}},
author = {Yijun Zhang and Siyu Liu and Wenhao Wang and Shufeng Li and Pingnan Dou and Shiyun Liu and Lei Wu and Xinjie Bu and Xuehao Zhou and Chenyi Jiang and Jianying Li and Fujun Zhao},
journal = {Cell \& Bioscience},
year = {2026},
month = aug,
doi = {10.1186/s13578-026-01627-7},
url = {https://doi.org/10.1186/s13578-026-01627-7},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Macrophage-derived IL-1β drives endothelial-mesenchymal transition in diabetes mellitus erectile dysfunction
AU - Yijun Zhang
AU - Siyu Liu
AU - Wenhao Wang
AU - Shufeng Li
AU - Pingnan Dou
AU - Shiyun Liu
AU - Lei Wu
AU - Xinjie Bu
AU - Xuehao Zhou
AU - Chenyi Jiang
AU - Jianying Li
AU - Fujun Zhao
PY - 2026
DA - 2026/08/09
JO - Cell & Bioscience
DO - 10.1186/s13578-026-01627-7
UR - https://doi.org/10.1186/s13578-026-01627-7
AB - Background: Diabetes mellitus erectile dysfunction (DMED) is frequently accompanied by corpus cavernosum (CC) fibrosis and endothelial dysfunction; however, the cellular drivers and molecular mechanisms underlying these pathological changes remain incompletely understood. Endothelial-to-mesenchymal transition (EndMT), a phenotypic conversion in which endothelial cells lose endothelial characteristics and acquire mesenchymal features, has emerged as a key contributor to tissue fibrosis under inflammatory and metabolic stress conditions. Macrophages (Mφ), the predominant immune cell population in CC tissue in diabetes, are major sources of pro-inflammatory cytokines and may promote fibrosis by driving EndMT. This study investigated the role and mechanisms of Mφ in CC fibrosis during DMED and explored potential therapeutic targets. Results: In a streptozotocin-induced DMED rat model, erectile function was significantly impaired, as evidenced by a marked reduction in the maximum intracavernous pressure-to-mean arterial pressure (ICP-to-MAP) ratio. This functional deterioration resulted from pronounced Mφ infiltration and enhanced fibrotic remodeling in CC. Pharmacological depletion of Mφ using clodronate liposomes significantly restored erectile function and increased the smooth muscle-to-collagen ratio. In vitro, co-culture of corpus cavernosum endothelial cells (CCEC) with Mφ under high-glucose (HG) conditions impaired endothelial tube formation and sprouting capacity, accelerated wound closure, and induced EndMT, characterized by downregulation of endothelial markers (CD34 and VE-cadherin) and upregulation of mesenchymal markers (Vimentin and α-SMA). RNA sequencing identified enrichment of interleukin-1 (IL-1)–related responses and Nuclear factor kappa B (NF-κB) signaling during EndMT. Further analyses demonstrated that HG stimulated Mφ to upregulate and secrete interleukin-1 beta (IL-1β), which in turn induced EndMT in CCEC accompanied by activation of NF-κB signaling, as evidenced by increased phosphorylation of p65 and IκBα. Pharmacological inhibition of the IL-1 receptor or NF-κB signaling effectively attenuated EndMT in vitro. Notably, in vivo administration of the IL-1 receptor antagonist Anakinra significantly improved erectile function and suppressed EndMT-associated molecular changes in DMED rats. Conclusions: Mφ-derived IL-1β promotes cavernosal fibrosis and erectile dysfunction in diabetes by inducing EndMT through activation of the NF-κB pathway. Targeting the IL-1β/NF-κB/EndMT axis represents a promising therapeutic strategy for the treatment of DMED. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13578-026-01627-7.
SN - 2045-3701
ER -