Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis

Mbanefo, Evaristus C. and Le, Loc and Pennington, Luke F. and Odegaard, Justin I. and Jardetzky, Theodore S. and Alouffi, Abdulaziz and Falcone, Franco H. and Hsieh, Michael H. (2018) Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis. FASEB Journal, 32 (8). pp. 4408-4419. ISSN 1530-6860

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Abstract

Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but systemically administered IL-4 causes significant side effects. We hypothesized that the Schistosoma haematobium homolog of Interleukin-4-inducing principle from Schistosoma mansoni Eggs (H-IPSE), would reduce IHC and associated bladder pathology. IPSE binds IgE on basophils and mast cells, triggering IL-4 secretion by these cells. IPSE is also an “infiltrin”, translocating into the host nucleus to modulate gene transcription. Mice were administered IL-4, H-IPSE protein or its nuclear localization sequence (NLS) mutant with or without neutralizing anti-IL-4 antibody, or MESNA, followed by ifosfamide. Bladder tissue damage and hemoglobin content were measured. Spontaneous and evoked pain, urinary frequency and gene expression were assessed. Pain behaviors were interpreted in a blinded fashion. One dose of H-IPSE was superior to MESNA and IL-4 in suppressing bladder hemorrhage in an IL-4-and NLS-dependent fashion, and comparable to MESNA in dampening ifosfamide-triggered pain behaviors in an NLS-dependent manner. H-IPSE also accelerated urothelial repair following IHC. Our work represents the first therapeutic exploitation of a uropathogen-derived host modulatory molecule in a clinically relevant bladder disease model, and indicates that IPSE may be an alternative to MESNA for mitigating CHC.

Item Type: Article
Keywords: Infiltrin; Anti-inflammation; Ifosfamide; Allodynia; Urothelial repair
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number: https://doi.org/10.1096/fj.201701415R
Depositing User: Falcone, Franco
Date Deposited: 27 Sep 2018 10:21
Last Modified: 27 Sep 2018 10:23
URI: http://eprints.nottingham.ac.uk/id/eprint/50318

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