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Int J Biol Sci 2023; 19(11):3441-3455. doi:10.7150/ijbs.85089 This issue Cite

Research Paper

Rapamycin and Low-dose IL-2 Mediate an Immunosuppressive Microenvironment to Inhibit Benign Prostatic Hyperplasia

Tianyu Cao^1#, Feng Xie^2#, Youwei Shi^1#, Junhao Xu^1#, Yi Liu³, Di Cui¹, Fang Zhang¹, Lihui Lin⁴, Weize Li⁴, Yanting Gao⁴, Yuan Ruan¹, Xiaohai Wang¹, Yiping Zhu¹, Bangmin Han¹, Shujie Xia¹, Wenhuan Guo^5✉, Bin Li^{6,7,8,9,10,11✉}, Yifeng Jing^1✉

1. Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3. Department of Plastic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4. Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
5. Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
6. Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
7. Department of Thoracic Surgery, Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
8. Institute of Arthritis Research, Guanghua Integrative Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
9. Department of Integrated TCM & Western Medicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.
10. Henan Key Laboratory for Digestive Organ Transplantation, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
11. Shenzhen Key Laboratory of Immunity and Inflammatory Diseases, Shenzhen, China.
^#These authors contributed equally to this article.

✉ Corresponding authors: E-Mail: jingyifengedu.cn (Yifeng Jing), binliedu.cn (Bin Li), guowenhuansjtu.edu.cn (Wenhuan Guo). Telephone number: +86-13918839913 (Yifeng Jing), +86-18019287551 (Bin Li), +86-13651972685 (Wenhuan Guo).

Abstract

Benign prostatic hyperplasia (BPH) is a condition that becomes more common with age and manifests itself primarily as the expansion of the prostate and surrounding tissues. However, to date, the etiology of BPH remains unclear. In this respect, we performed single-cell RNA sequencing of prostate transition zone tissues from elderly individuals with different prostate volumes to reveal their distinct tissue microenvironment. Ultimately, we demonstrated that a reduced Treg/CD4+ T-cell ratio in the large-volume prostate and a relatively activated immune microenvironment were present, characterized partially by increased expression levels of granzymes, which may promote vascular growth and profibrotic processes and further exacerbate BPH progression. Consistently, we observed that the prostate gland of patients taking immunosuppressive drugs usually remained at a smaller volume. Furthermore, in mouse models, we confirmed that both suppression of the immune system with rapamycin and induction of Treg proliferation with low doses of IL-2 therapy indeed prevented the progression of BPH. Taken together, our findings suggest that an activated immune microenvironment is necessary for prostate volume growth and that Tregs can reverse this immune activation state, thereby inhibiting the progression of BPH.

Keywords: BPH, Immune microenvironment, Treg

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