Pathogenic Roles of CXCL10 in Experimental Autoimmune Prostatitis by Modulating Macrophage Chemotaxis and Cytokine Secretion.

Xiaoliang Hua,Chaozhao Liang,Shengdong Ge,Xianguo Chen,Jiong Zhang,Fan Mo,Li Zhang,Cheng Yang,Meng Zhang,Ligang Zhang,Sheng Tai

doi:10.3389/fimmu.2021.706027

Abstract

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is an inflammatory immune disease characterized by intraprostatic leukocyte infiltration and pelvic or perineal pain. Macrophages play vital roles in the pathogenesis of CP/CPPS. However, the mechanisms controlling the activation and chemotaxis of macrophages in CP/CPPS remain unclear. This study aimed to investigate the roles of the CXCL10/CXCR3 pathway in the activation and chemotaxis of macrophages in CP/CPPS patients. The serums of CP/CPPS patients and healthy volunteers were collected and measured. Results showed that CXCL10 expression was significantly elevated and correlated with the severity of CP/CPPS patients. The experimental autoimmune prostatitis (EAP) model was generated, and adeno-associated virus and CXCR3 inhibitors were used to treat EAP mice. Immunofluorescence, flow cytometry, and Western blotting were used to analyze the functional phenotype and regulation mechanism of macrophages. Results showed that CXCL10 deficiency ameliorates EAP severity by inhibiting infiltration of macrophages to prostate. Moreover, CXCL10 could induce macrophage migrations and secretions of proinflammatory mediators via CXCR3, which consequently activated the downstream Erk1/2 and p38 MAPK signaling pathways. We also showed that prostatic stromal cell is a potential source of CXCL10. Our results indicated CXCL10 as an important mediator involved in inflammatory infiltration and pain symptoms of prostatitis by promoting the migration of macrophages and secretion of inflammatory mediators via CXCR3-mediated ERK and p38 MAPK activation.

Highlights

Prostatitis is the most common urologic disease in men under 50 years old, accounting for 8% of urologist visits [1,2,3]
We showed that CXCL10 could activate extracellular signal-regulated kinase (Erk) and p38-mitogen-activated protein kinase (MAPK) signaling pathways by binding to CXCR3 to enhance the accumulation of inflammatory cells and secretion of inflammatory mediators
Cytokine IFN-g has been postulated to play an important role in the pathogenesis of Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) patients and the experimental autoimmune prostatitis (EAP) model [17, 18, 31]

Summary

Introduction

Prostatitis is the most common urologic disease in men under 50 years old, accounting for 8% of urologist visits [1,2,3]. The intraprostatic inflammatory infiltrate in the EAP model is characterized by CD4+ T cells and macrophages [13, 14], suggesting its vital roles in the development of EAP [15]. These cells could interact with other immune and resident cells, including epithelial and stromal cells by secreting cytokines and chemokines, leading to a boost in the production of proinflammatory cytokines and chemokines. IFN-g-deficient mice showed a significantly decreased number of leukocyte infiltrates in the prostate in the EAP model, owing to impairing the abilities of T cells for homing to the prostate gland [18]. The molecules and specific mechanisms regulated by IFN-g signaling remain to be explored

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Conclusion