IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways

Mbanefo, Evaristus C.; Le, Loc; Zee, Rebecca; Banskota, Nirad; Ishida, Kenji; Pennington, Luke F.; Odegaard, Justin I.; Jardetzky, Theodore S.; Alouffi, Abdulaziz; Falcone, Franco H.; Hsieh, Michael H.

Abstract

Ifosfamide and other oxazaphosphorines can result in hemorrhagic cystitis, a constellation of complications caused by acrolein metabolites. We previously showed that a single dose of IPSE (Interleukin-4-inducing principle from Schistosoma eggs), a schistosome-derived host modulatory protein, can ameliorate ifosfamide-related cystitis; however, the mechanisms underlying this urotoxicity and its prevention are not fully understood. To provide insights into IPSE’s protective mechanism, we undertook transcriptional profiling of bladders from ifosfamide-treated mice, with or without pretreatment with IPSE or IPSE-NLS (a mutant of IPSE lacking nuclear localization sequence). Ifosfamide treatment upregulated a range of proinflammatory genes. The IL-1β-TNFα-IL-6 proinflammatory cascade via NFκB and STAT3 pathways was identified as the key driver of inflammation. The NRF2-mediated oxidative stress response pathway, which regulates heme homoeostasis and expression of antioxidant enzymes, was highly activated. Anti-inflammatory cascades, namely Wnt, Hedgehog and PPAR pathways, were downregulated. IPSE drove significant downregulation of major proinflammatory pathways including the IL-1β-TNFα-IL-6 pathways, interferon signaling, and reduction in oxidative stress. IPSE-NLS reduced inflammation but not oxidative stress. Taken together, we have identified signatures of acute-phase inflammation and oxidative stress in ifosfamide-injured bladder, which are reversed by pretreatment with IPSE. This work revealed several pathways that could be therapeutically targeted to prevent ifosfamide-induced hemorrhagic cystitis.

Citation

Mbanefo, E. C., Le, L., Zee, R., Banskota, N., Ishida, K., Pennington, L. F., …Hsieh, M. H. (2019). IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways. Scientific Reports, 9, Article 1586. https://doi.org/10.1038/s41598-018-38274-z

• Journal Article Type: Article
• Acceptance Date: Dec 18, 2018
• Online Publication Date: Feb 7, 2019
• Publication Date: Feb 7, 2019
• Deposit Date: Feb 8, 2019
• Publicly Available Date: Feb 8, 2019
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Article Number: 1586
• DOI: https://doi.org/10.1038/s41598-018-38274-z
• Public URL: https://nottingham-repository.worktribe.com/output/1425545
• Publisher URL: https://www.nature.com/articles/s41598-018-38274-z
• Additional Information: Received: 28 September 2018; Accepted: 18 December 2018; First Online: 7 February 2019; : The authors declare no competing interests.