The roles of MCP-1/CCR2 mediated macrophage recruitment and polarization in bladder outlet obstruction (BOO) induced bladder remodeling

Abstract

Bladder outlet obstruction (BOO) can lead to alternation of bladder structure and function, known as bladder remodeling. Macrophage is a heterogeneous cell type and implicated in immunity regulating and tissue repairment. The relationship between macrophage and BOO remains unclear. We determined the pivotal role of macrophage recruitment and polarization in bladder remodeling. Sprague-Dawley rats underwent surgical operation of a BOO for either 1, 3, 6 weeks and were compared with sham-operated rats. The BOO rats in the experimental group were orally administrated with 5 mg/kg RS-504393, a C-C chemokine receptor (CCR2) antagonist, for 6 weeks, and the rats in the control group were treated with vehicle. Bladder tissues were harvested for assays of flow cytometry, quantitative reverse transcription polymerase chain reaction, histological examinations, immunohistochemistry staining and immunofluorescence. After induction of BOO, M1 macrophages were predominantly observed at inflammatory stage while M2 macrophages were mainly found during fibrosis stage. Flow cytometry analysis revealed that the ratio of M1/M2 significantly increased at 3 weeks (P = 0.0013) when compared to the sham-operated group. Interestingly, our results showed that M2 macrophages promoted BOO-induced fibrosis through indirectly secreting TGF-β and directly transforming to collagen-producing myofibroblast. Additionally, RS-504393 treatment significantly decreased the number of M1 and M2 macrophage infiltration in bladder tissue, and bladder fibrosis was attenuated by RS-504393 treatment compared with that in the vehicle-treated rats. In summary, macrophages play a pivotal role in bladder remodeling and targeting MCP-1/CCR2 signaling pathway might be a therapeutic strategy for human bladder fibrosis.