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CXCR3 antagonist AMG487 ameliorates experimental autoimmune prostatitis by diminishing Th1 cell differentiation and inhibiting macrophage M1 phenotypic activation

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.

 

Comments:

The study you provided investigates the potential therapeutic effects of a CXCR3 antagonist called AMG487 in a mouse model of experimental autoimmune prostatitis (EAP), which is used as a model for chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). Here are the key findings and conclusions of the study:

1. CXCR3 Expression: The researchers observed high expression of CXCR3, a receptor involved in immune and inflammatory responses, in human benign prostate tissues with inflammation and in the prostate tissues of EAP mice. The severity of inflammation correlated with the elevated levels of CXCR3.

2. Effect of AMG487 Treatment: The study found that treatment with the CXCR3 antagonist AMG487 improved the inflammatory changes and alleviated pelvic pain in EAP mice.

3. Inhibition of Th1 Cell Differentiation: AMG487 treatment was shown to inhibit the differentiation of T helper type 1 (Th1) cells, a subset of immune cells involved in pro-inflammatory responses. This effect was mediated through the IL-12/STAT4 pathway, a signaling pathway known to regulate Th1 cell differentiation.

4. Inhibition of Pro-inflammatory M1 Macrophages: AMG487 treatment also inhibited the activation of pro-inflammatory M1 macrophages, another type of immune cell involved in promoting inflammation. This inhibition was achieved by blocking the lipopolysaccharide (LPS)/NF-κB p65 signaling pathway, which is responsible for M1 macrophage activation.

5. Inhibition of Inflammatory Mediator Secretion: AMG487 treatment led to a reduction in the secretion of inflammatory mediators in EAP mice, further supporting its anti-inflammatory effects.

Based on these findings, the study concludes that the CXCR3 antagonist AMG487 has the potential to be an effective therapeutic agent for the prevention and treatment of EAP. By inhibiting Th1 cell differentiation and M1 macrophage activation, AMG487 can ameliorate inflammatory changes and pelvic pain associated with EAP. These results suggest that targeting CXCR3 may hold promise for the development of therapies for CP/CPPS.

Related Products

Cat.No. Product Name Information
S8682 AMG 487 AMG 487 is an orally active and selective CXC chemokine receptor 3 (CXCR3) antagonist that inhibits the binding of IP-10 (CXCL10) and ITAC (CXCL11) to CXCR3 with IC50 of 8.0 nM and 8.2 nM, respectively.

Related Targets

CXCR