2. Academic Validation
  3. S100A9 as a potential novel target for experimental autoimmune cystitis and interstitial cystitis/bladder pain syndrome

S100A9 as a potential novel target for experimental autoimmune cystitis and interstitial cystitis/bladder pain syndrome

  • Biomark Res. 2025 May 9;13(1):72. doi: 10.1186/s40364-025-00763-5.
Jiang Zhao # 1 2 3,  Mi Zhou # 4 5,  Chengfei Yang # 6,  Yang-Wuyue Liu 4,  Teng Yang 4,  Bishao Sun 7,  Benyi Li 8,  Ji Zheng 7,  Shuangshuang Dai 9,  Zhenxing Yang 10,  Xiangwei Wang 11
Affiliations

Affiliations

  • 1 Department of Urology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, PR China. urologyzhaoj@sohu.com.
  • 2 Department of Urology, Second Affiliated Hospital, Army Military Medical University, Chongqing, 400037, PR China. urologyzhaoj@sohu.com.
  • 3 Department of Urology, The University of Kansas Medical Center, Kansas City, KS, 66160, USA. urologyzhaoj@sohu.com.
  • 4 Department of Biochemistry and Molecular Biology, Army Military Medical University, Chongqing, 400038, PR China.
  • 5 Department of Central Laboratory, Qianjiang Hospital, Chongqing University, Chongqing, RP, 409000, China.
  • 6 Department of Thoracic Surgery, Second Affiliated Hospital, Army Military Medical University, Chongqing, 400037, PR China.
  • 7 Department of Urology, Second Affiliated Hospital, Army Military Medical University, Chongqing, 400037, PR China.
  • 8 Department of Urology, The University of Kansas Medical Center, Kansas City, KS, 66160, USA.
  • 9 Department of Biochemistry and Molecular Biology, Army Military Medical University, Chongqing, 400038, PR China. tmmubiodss@tmmu.edu.cn.
  • 10 Department of Blood Transfusion, Irradiation Biology Laboratory, Second Affiliated Hospital, Army Military Medical University, Chongqing, 400037, PR China. yangzx88@tmmu.edu.cn.
  • 11 Department of Urology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, PR China. winn0324@gmail.com.
  • # Contributed equally.
PMID: 40346703 DOI: 10.1186/s40364-025-00763-5
Abstract

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory disease of the bladder for which no effective therapy is currently available. Understanding the pathogenesis of IC/BPS and identifying effective intervention targets are of great clinical importance for its effective treatment. Our work focuses on elucidating the key targets and underlying mechanisms of IC/BPS.

Methods: We established an experimental autoimmune cystitis (EAC) mouse model and generated gene knockout mice to elucidate key mediators triggering chronic inflammatory damage in IC/BPS through using single-cell RNA Sequencing, proteomic Sequencing, and Molecular Biology experiments.

Results: Our study revealed that the infiltration and activation of macrophages, T cells, and mast cells exacerbated inflammatory bladder damage in both IC/BPS and EAC mice. Notably, cell-cell communication among bladder immune cells was significantly enhanced in EAC mice. Macrophages, as the main cell types altered in EAC mice, received and transmitted the most intensity signalling. Mechanistically, macrophages synthesized and secreted S100A9, which in turn facilitated macrophage polarization and promoted the production of pro-inflammatory cytokines. S100A9 emerged as an important pro-inflammatory and pathogenic molecule in IC/BPS and EAC. Further analysis demonstrated that S100A9 activation enhanced the inflammatory response and exacerbated bladder tissue damage in IC/BPS patients and EAC mice via TLR4/NF-κB and TLR4/p38 signalling pathways. Importantly, inhibition of S100A9 with paquinimod, as well as genetic knockout of S100A9, significantly attenuated the pathological process.

Conclusions: S100A9 is an important pro-inflammatory and pathogenic molecule in IC/BPS and EAC. Targeting S100A9-initiated signalling pathways may offer a novel therapeutic strategy for IC/BPS.

Keywords

Autoimmune disease; Experimental autoimmune cystitis; Inflammation; Interstitial cystitis/bladder pain syndrome; S100A9.

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