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4-Methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy for chronic prostatitis
Jing Chen1, Jialin Meng1, Chen Jin1
1Department of Urology, The First Affiliated Hospital of Anhui Medical University, Institute of Urology, and Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China.
Insights
Hyaluronan (HA) is elevated in chronic prostatitis patients and drives disease severity. Inhibiting HA synthesis with 4-methylumbelliferone (4-MU) reduced inflammation and Th1 cell activity, suggesting a new therapeutic target for chronic prostatitis.
Area of Science:
- Urology
- Immunology
- Biochemistry
Background:
- Hyaluronan (HA), an extracellular matrix component, is implicated in chronic inflammatory conditions.
- Its role in the pathogenesis of chronic prostatitis, however, remains largely uncharacterized.
Purpose of the Study:
- To investigate the impact of Hyaluronan (HA) on the pathogenesis of chronic prostatitis.
- To explore the potential of targeting HA synthesis as a therapeutic strategy.
Main Methods:
- Assessed HA levels in peripheral blood serum of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) patients and correlated with disease severity.
- Induced an experimental autoimmune prostatitis (EAP) mouse model and treated with 4-methylumbelliferone (4-MU), a HA synthesis inhibitor.
- Utilized RNA sequencing and weighted gene co-expression network analysis (WGCNA) to identify key pathways and genes involved in EAP pathogenesis.
Main Results:
- Elevated HA levels were observed in CP/CPPS patients, correlating positively with pain, urinary symptoms, and reduced quality of life.
- In EAP mice, 4-MU treatment reduced prostate inflammation and the proportion of Th1 cells.
- WGCNA identified specific gene modules associated with EAP, and pathway analysis indicated HA activates the cell cycle pathway, promoting Th1 cell proliferation.
Conclusions:
- Hyaluronan (HA) is a significant factor in CP/CPPS pathogenesis, linked to inflammation and symptom severity.
- Targeting HA synthesis with 4-MU demonstrates therapeutic potential by suppressing the cell cycle pathway and Th1 cell activity.
- These findings suggest novel therapeutic avenues for managing chronic prostatitis.
Background:
Hyaluronan (HA), an extracellular matrix component, accumulates in most chronic inflammatory tissues. Here, we studied the impact of HA on the pathogenesis of chronic prostatitis.
Materials And Methods:
First, we sorted demographic characteristics and peripheral blood serum samples from patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) to assess the relationship between the levels of HA in peripheral blood serum and the severity of inflammation in patients. Second, we induced an experimental autoimmune prostatitis (EAP) mouse model and treated the mice with 4-methylumbelliferone (4-MU) (200 mg/kg/day). After the mice were sacrificed, RNA from Th1 cells of the mouse spleens was extracted for RNA sequencing. We used weighted gene co-expression network analysis (WGCNA) to identify co-expressed gene modules and hub-gene related to the pathogenesis of EAP. The expression of critical genes associated with the identified pathway was confirmed by using western blot analysis.
Results:
HA was significantly more highly expressed in CP/CPPS patients than in healthy volunteers and positively correlated with the severity of pain, urination symptoms, and quality of life. Besides, the protein expression of HA was significantly higher in prostate tissues derived from EAP models than in those derived from controls. 4-MU, an oral inhibitor of HA synthesis, relieved immunocyte infiltration to the prostate and significantly reduced the proportion of Th1 cells. Based on the WGCNA, we identified 18 co-expression modules and identified that the Grey60 and brown modules were positively associated with the EAP and negatively associated with the Control and 4-MU-treated groups. Pathway enrichment analyses and western blot assays proved that HA potentially activated the cell cycle pathway, increasing the proportion of Th1 cells promoting chronic prostatitis pathogenesis, while these processes were reversed by 4-MU treatment.
Conclusions:
Our results suggest that HA is elevated in patients with CP/CPPS compared with healthy controls and that targeting HA through 4-MU suppresses the activity of the cell cycle-related pathway, potentially by decreasing the proportion of Th1 cells and relieving chronic prostatitis. Our findings might inspire the clinical treatment of chronic prostatitis.
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