CXCR3 antagonist AMG487 ameliorates experimental autoimmune prostatitis by diminishing Th1 cell differentiation and
Xiaoliang Hua1,2,3, Jiong Zhang1,2,3, Shengdong Ge1,2,3
1Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Background:
Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is an inflammatory immune disease that is characterized by infiltrating inflammatory cells in the prostate and pelvic or by perineal pain. Receptor CXCR3modulates immune and inflammatory responses; however, the effects of CXCR3 antagonist AMG487 in the context of CP/CPPS are unknown. Therefore, we investigated the effect of AMG487 in experimental autoimmune prostatitis (EAP) mice and explored the potential functional mechanisms.
Methods:
The EAP model was induced by intradermally injecting a mixture of prostate antigens and complete Freund's adjuvant on Days 0 and 28. To evaluate the effect of AMG487 on EAP mice, treatment with AMG487 and vehicle solution was conducted for the indicated period. Then, procedures were performed, including behavioral test, to evaluate the pain response to stimulation before the mice were killed and a histological assessment to evaluate the inflammation after the mice were killed. Immunofluorescence, flow cytometry, and Western blot assay were used to analyze the functional phenotype and regulation mechanism of AMG487 on T helper type 1 (Th1) cells and macrophages.
Results:
We found high expression of CXCR3 in human benign prostate tissues with inflammation and EAP mice. The elevated CXCR3 in prostate tissues correlates with the severity of inflammation. CXCR3 antagonist AMG487 treatment ameliorated the inflammatory changes and the pelvic pain of EAP mice. AMG487 inhibits Th1 cell differentiation through the IL-12/STAT4pathway and inhibits pro-inflammatory M1 macrophages through the lipopolysaccharide/NF-κB p65signaling. AMG487 could inhibit the secretion of inflammatory mediators in EAP mice.
Conclusion:
CXCR3 antagonist AMG487 could ameliorate the inflammatory changes and the pelvic pain of EAP mice by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation. Thus, the results imply that AMG487 has the potential as an effective therapeutic agent in the prevention and treatment of EAP.
Insights
The CXCR3 antagonist AMG487 effectively reduced inflammation and pelvic pain in experimental autoimmune prostatitis (EAP) mice. This suggests AMG487 may be a promising treatment for chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS).
Area of Science:
- Immunology
- Urology
- Pharmacology
Background:
- Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is an inflammatory condition causing pelvic pain.
- Receptor CXCR3 plays a role in immune responses, but its role in CP/CPPS and the effect of its antagonist AMG487 are unknown.
Purpose of the Study:
- To investigate the therapeutic potential of the CXCR3 antagonist AMG487 in a mouse model of autoimmune prostatitis (EAP).
- To explore the underlying mechanisms of AMG487's action on immune cells involved in prostatitis.
Main Methods:
- Experimental autoimmune prostatitis (EAP) was induced in mice using prostate antigens.
- Mice were treated with AMG487 or vehicle, followed by behavioral tests for pain and histological analysis for inflammation.
- Immunofluorescence, flow cytometry, and Western blot were used to analyze T helper 1 (Th1) cells and macrophages.
Main Results:
- High CXCR3 expression was observed in inflamed prostate tissues, correlating with inflammation severity.
- AMG487 treatment significantly reduced pelvic pain and inflammation in EAP mice.
- AMG487 inhibited Th1 cell differentiation via the IL-12/STAT4 pathway and M1 macrophage activation via the LPS/NF-κB pathway, reducing inflammatory mediators.
Conclusions:
- The CXCR3 antagonist AMG487 ameliorates inflammation and pelvic pain in EAP mice.
- AMG487's therapeutic effect is mediated by suppressing Th1 cell differentiation and M1 macrophage activation.
- AMG487 shows potential as an effective therapeutic agent for EAP and potentially CP/CPPS.
More Related Videos
07:41A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
10:35Assessment of Antibody-based Drugs Effects on Murine Bone Marrow and Peritoneal Macrophage Activation
Published on: December 26, 2017