The abnormal CXCL13/CXCR5 axis is involved in many inflammatory diseases and its selective inhibitor, TAK-799 has exhibited strong anti-inflammatory potency. The sequencing of clinical specimens from interstitial cystitis/bladder pain syndrome (IC/BPS) has shown that CXCL13 and CXCR5 are highly expressed, but the role of CXCL13/CXCR5 axis in IC/BPS has not been rarely reported. Therefore, in this study, we analyzed the GSE11783 sequencing data of IC/BPS patients and investigate the role and mechanism of CXCL13/CXCR5 axis and TAK-779 in the mouse model of experimental autoimmune cystitis (EAC). We verified that CXCL13 and CXCR5 were significantly up-regulated in EAC model. EAC mice exhibited increased bladder inflammatory factors (IL-6, TNF-α, IL-1β), apoptosis-related proteins (Bax, Caspase-3, Caspase-8), frequency of voiding. Using TAK779 to block CXCL13/CXCR5 axis significantly attenuated these inflammatory damages and efficiently improved bladder function (significant reduction in micturition frequency, significant prolongation of inter-contraction interval). Further investigation showed that inhibiton of JNK and NF-kappaB activation, the bioinformatics analysis-indicated downstream signaling of CXCL13/CXCR5 axis, is responsible for the protective effect of TAK779. Taken together, we demonstrate that activation of the CXCL13/CXCR5 axis is involved in the pathophysiology of IC/BPS and EAC. Blocking CXCL13/CXCR5 axis activation by TAK-779 reduces bladder inflammation and improves bladder function in EAC mice.
Biochemical pharmacology. 2022 Apr 19 [Epub ahead of print]
Jiang Zhao, Shan Chen, Chengfei Yang, Mi Zhou, Teng Yang, Bishao Sun, Jingzheng Zhu, Hengshuai Zhang, Qudong Lu, Longkun Li, Zhenxing Yang, Bo Song, Wenhao Shen, Shanhong Yi, Shuangshuang Dai
Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China; Department of Urology, Second Affiliated Hospital,Army Military Medical University, Chongqing, 400037, PR China., Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China., Department of Urology, Second Affiliated Hospital,Army Military Medical University, Chongqing, 400037, PR China., Department of Urology, Southwest Hospital, Army Medical University, Chongqing 400038, PR China., Department of Biochemistry and Molecular Biology, Army Medical University, Chongqing, 400038, PR China. Electronic address: .