Targeting CXCL12/CXCR4 Signaling with AMD3100 Might Selectively Suppress CXCR4+ T-Cell Chemotaxis Leading to the Alleviation of Chronic Prostatitis.

Chronic nonbacterial prostatitis (CNP) has a high incidence, low cure rate, and unclear pathogenesis. Here, we aimed to systematically identify effective diagnostic and therapeutic targets for CNP.

Prostate tissues were obtained from established mouse models and negative controls and were used for mRNA array sequencing and immunohistochemistry (IHC) staining. Predominant pathways were identified based on pathway enrichment analysis and pharmaceutical experiments. We also investigated the functional role of CXCL12 on CP, a critical factor belonging to the predominant chemotaxis pathway, and employed IHC staining to explore the influence of the CXCL12/CXCR4 axis on the activation of the NF-κB, AKT, and STAT3 signaling pathways. Serum samples derived from both CNP cases and healthy controls were used to determine the secretion level of CXCL12.

By employing mRNA array sequencing and immunohistochemistry, we found that CXCR4, CXCL12, CD44, and OFLM4 were highly expressed in the infiltrated inflammatory T cells of the prostate tissues generated from CNP mice, while they were rarely expressed on the epithelial cells. Based on the pathway enrichment results, we applied pathway inhibitors to suppress the activity of these classic pathways. We found that targeting the CXCL12/CXCR4 axis with its specific antagonist AMD3100 remarkably alleviated inflammatory infiltration of the prostate in CNP models. Similar results were obtained when we replaced AMD3100 with adenovirus-associated virus (AAV)-shCxcl12. To clarify the potential mechanisms of how the CXCL12/CXCR4 axis influences the pathogenesis of CNP, we tested the classical downstream pathways. The results suggested that p-Akt, p-STAT3, and p-NF-κB were more highly expressed on the inflammatory cells of the prostate derived from the CNP model and were partly suppressed after applying AMD3100 or delivering AAV-shCxcl12, indicating that the CXCL12/CXCR4 axis potentially functioned through AKT/NF-κB and STAT3 signaling to influence the pathogenesis of CNP.

Our study provides potential diagnostic biomarkers and therapeutic targets for CNP.

Journal of inflammation research. 2022 Apr 21*** epublish ***

Meng Zhang, Yi Liu, Jing Chen, Lei Chen, Li Zhang, Xianguo Chen, Zongyao Hao, Chaozhao Liang

Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.

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