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Papers of the Week


Papers: 25 Jul 2020 - 31 Jul 2020


Animal Studies


2020 Jul 22


Cells


9


8

Cystitis-Related Bladder Pain Involves ATP-Dependent HMGB1 Release from Macrophages and Its Downstream HS/Ca3.2 Signaling in Mice.

Authors

Hiramoto S, Tsubota M, Yamaguchi K, Okazaki K, Sakaegi A, Toriyama Y, Tanaka J, Sekiguchi F, Ishikura H, Wake H, Nishibori M, Du Nguyen H, Okada T, Toyooka N, Kawabata A
Cells. 2020 Jul 22; 9(8).
PMID: 32707767.

Abstract

Cystitis-related bladder pain involves RAGE activation by HMGB1, and increased Ca3.2 T-type Ca channel activity by HS, generated by upregulated cystathionine-γ-lyase (CSE) in mice treated with cyclophosphamide (CPA). We, thus, investigated possible crosstalk between the HMGB1/RAGE and CSE/HS/Ca3.2 pathways in the bladder pain development. Bladder pain (nociceptive behavior/referred hyperalgesia) and immuno-reactive CSE expression in the bladder were determined in CPA-treated female mice. Cell signaling was analyzed in urothelial T24 and macrophage-like RAW264.7 cells. The CPA-induced bladder pain was abolished by pharmacological inhibition of T-type Ca channels or CSE, and genetic deletion of Ca3.2. The CPA-induced CSE upregulation, as well as bladder pain was prevented by HMGB1 inactivation, inhibition of HMGB1 release from macrophages, antagonists of RAGE or P2X/P2X receptors, and N-acetylcysteine, an antioxidant. Acrolein, a metabolite of CPA, triggered ATP release from T24 cells. Adenosine triphosphate (ATP) stimulated cell migration via P2X/P2X, and caused HMGB1 release via P2X in RAW264.7 cells, which was dependent on p38MAPK/NF-κB signaling and reactive oxygen species (ROS) accumulation. Together, our data suggest that CPA, once metabolized to acrolein, causes urothelial ATP-mediated, redox-dependent HMGB1 release from macrophages, which in turn causes RAGE-mediated CSE upregulation and subsequent HS-targeted Ca3.2-dependent nociceptor excitation, resulting in bladder pain.