Activation of CXCL13/CXCR5 axis aggravates experimental autoimmune cystitis and interstitial cystitis/bladder pain syndrome.

Abstract

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.

• Authors: 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
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 200 Pg. 115047 (06 2022) ISSN: 1873-2968 [Electronic] England
• PMID: 35452631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022. Published by Elsevier Inc.

Chemical References

• CXCR5 protein, mouse
• Chemokine CXCL13
• Cxcl13 protein, mouse
• Receptors, CXCR5

Topics

• Animals
• Autoimmune Diseases
• Chemokine CXCL13 (genetics)
• Cystitis
• Cystitis, Interstitial (metabolism)
• Disease Models, Animal
• Female
• Humans
• Male
• Mice
• Receptors, CXCR5 (genetics, metabolism)
• Signal Transduction