CXCR3 拮抗剂 AMG487 通过减少 Th1 细胞分化和抑制巨噬细胞 M1 表型激活来改善实验性自身免疫性前列腺炎。

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

机构信息

Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.

出版信息

Prostate. 2022 Sep;82(13):1223-1236. doi: 10.1002/pros.24395. Epub 2022 Jun 14.

DOI:10.1002/pros.24395

PMID:35700340

Abstract

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.

摘要

背景

慢性前列腺炎和慢性骨盆疼痛综合征（CP/CPPS）是一种炎症性免疫疾病，其特征是前列腺和骨盆浸润性炎症细胞或会阴疼痛。受体 CXCR3 调节免疫和炎症反应；然而，CXCR3 拮抗剂 AMG487 在 CP/CPPS 中的作用尚不清楚。因此，我们研究了 AMG487 在实验性自身免疫性前列腺炎（EAP）小鼠中的作用，并探讨了其潜在的功能机制。

方法

通过在第 0 天和第 28 天皮内注射前列腺抗原和完全弗氏佐剂混合物诱导 EAP 模型。为了评估 AMG487 对 EAP 小鼠的影响，在指定时间内用 AMG487 和载体溶液进行治疗。然后，进行程序，包括行为测试，以评估在杀死小鼠之前对刺激的疼痛反应，以及在杀死小鼠后进行组织学评估以评估炎症。免疫荧光、流式细胞术和 Western blot 分析用于分析 AMG487 对 Th1 细胞和巨噬细胞的功能表型和调节机制。

结果

我们发现 CXCR3 在有炎症的人良性前列腺组织和 EAP 小鼠中高表达。前列腺组织中升高的 CXCR3 与炎症的严重程度相关。CXCR3 拮抗剂 AMG487 治疗改善了 EAP 小鼠的炎症变化和骨盆疼痛。AMG487 通过 IL-12/STAT4 途径抑制 Th1 细胞分化，并通过脂多糖/NF-κB p65 信号抑制促炎 M1 巨噬细胞。AMG487 可抑制 EAP 小鼠中炎症介质的分泌。