HO-1 alleviates neuroinflammation and cystitis-related symptoms in cyclophosphamide-induced cystitis via the SIRT1 pathway
Research Square (Research Square)(2022)
摘要
Abstract Background Our previous study suggested that astrocytes and microglia are activated in the spinal dorsal horn (SDH) of interstitial cystitis/bladder pain syndrome (IC/BPS) rats and induce neuroinflammation by secreting proinflammatory cytokines. Heme oxygenase-1 (HO-1) plays a key role in inhibiting neuroinflammatory processes in the central nervous system and can activate silent information regulator 1 (SIRT1), which has an inhibitory effect on neuroinflammation; however, whether HO-1 alleviates neuroinflammation in IC remains unclear. This study aimed to elucidate the role of HO-1 in rat IC models and confirm whether SIRT1 mediates HO-1 function. Methods Rats were administered with cyclophosphamide (CYP) by systemic intraperitoneal injection to develop IC models. Hemin (inducer of HO-1) and Znpp (HO-1 inhibitor) were performed intraperitoneally 1-day prior to each CYP injection. EX-527 was injected intrathecally for 3 consecutive days to selectively inhibit SIRT1. We used the von Frey filament test to measure mechanical withdrawal threshold, and urinary frequency was assessed using urodynamic tests. HO-1, SIRT1, glial fibrillary acidic protein (an astrocyte marker), ionized calcium-binding adapter molecule (a microglia marker), phosphorylated (p)-c-Jun N-terminal kinase (JNK), p-p38, and proinflammatory cytokines [interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α] levels were assessed by western blot, and immunofluorescence was used to identify HO-1 and SIRT1 cellular localization. Results We observed downregulated HO-1 expression in the SDH of rats with CYP-induced cystitis, which was accompanied by neuroinflammation, mechanical allodynia, and urinary frequency. Additionally, HO-1 induction after hemin treatment suppressed glial cell activation and attenuated IL-1β, IL-6, and TNF-α expression by inhibiting activation of the JNK/p38 pathway, ultimately improving IC-related symptoms. Moreover, Znpp administration exacerbated inflammatory responses and pain sensitivity by inhibiting HO-1 activity. Furthermore, HO-1 positively regulated SIRT1 activation and alleviated IC-related symptoms, whereas the therapeutic effect of HO-1 upregulation was significantly impaired by SIRT1 inhibition. Conclusion HO-1 attenuated neuroinflammation, mechanical allodynia, and urinary frequency caused by glial activation in rats with CYP-induced cystitis by activating SIRT1 to inhibit JNK/p38 signaling.
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关键词
sirt1 pathway,neuroinflammation,cystitis-related,cyclophosphamide-induced
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