IPSE, a parasite-derived host immunomodulatory protein, is a potential therapeutic for hemorrhagic cystitis

Zee, Rebecca S.; Mbanefo, Evaristus C.; Le, Loc H.; Pennington, Luke F.; Odegaard, Justin; Jardetzky, Theodore S.; Alouffi, Abdulaziz; Akinwale, Jude; Falcone, Franco H.; Hsieh, Michael H.

Abstract

Chemotherapy-induced hemorrhagic cystitis is characterized by bladder pain and voiding dysfunction caused by hemorrhage and inflammation. Novel therapeutic options to treat hemorrhagic cystitis are needed. We previously reported that systemic administration of the Schistosomiasis haematobium-derived protein H-IPSEH06 (IL-4-inducing principle from Schistosoma mansoni eggs), is superior to 3 doses of MESNA in alleviating hemorrhagic cystitis. Based on prior reports by others on S. mansoni IPSE (M-IPSE) and additional work by our group, we reasoned that H-IPSE mediates its effects on hemorrhagic cystitis by binding IgE on basophils and inducing IL-4 expression, promoting urothelial proliferation, and translocating to the nucleus to modulate expression of genes implicated in relieving bladder dysfunction. We speculated that local bladder injection of the S. haematobium IPSE ortholog IPSEH03, hereafter called H-IPSEH03, might be more efficacious in preventing hemorrhagic cystitis compared to systemic administration of IPSEH06. We report that H-IPSEH03, like M-IPSE and H-IPSEH06, activates IgE-bearing basophils in an NFAT reporter assay, indicating activation of the cytokine pathway. Further, H-IPSEH03 attenuates ifosfamide-induced increases in bladder wet weight in an IL-4-dependent fashion. H-IPSEH03 relieves hemorrhagic cystitis-associated allodynia and modulates voiding patterns in mice. Finally, H-IPSEH03 drives increased urothelial cell proliferation suggesting that IPSE induces bladder repair mechanisms. Taken together, H-IPSEH03 may be a potential novel therapeutic to treat hemorrhagic cystitis by basophil activation, attenuation of allodynia and promotion of urothelial cell proliferation.

Citation

Zee, R. S., Mbanefo, E. C., Le, L. H., Pennington, L. F., Odegaard, J., Jardetzky, T. S., Alouffi, A., Akinwale, J., Falcone, F. H., & Hsieh, M. H. (2019). IPSE, a parasite-derived host immunomodulatory protein, is a potential therapeutic for hemorrhagic cystitis. AJP - Renal Physiology, 316(6), F1133-F1140. https://doi.org/10.1152/ajprenal.00468.2018

• Journal Article Type: Article
• Acceptance Date: Feb 19, 2019
• Online Publication Date: Feb 20, 2019
• Publication Date: May 20, 2019
• Deposit Date: May 7, 2019
• Publicly Available Date: May 8, 2019
• Journal: American Journal of Physiology-Renal Physiology
• Print ISSN: 1931-857X
• Electronic ISSN: 1522-1466
• Publisher: American Physiological Society
• Peer Reviewed: Peer Reviewed
• Volume: 316
• Issue: 6
• Pages: F1133-F1140
• DOI: https://doi.org/10.1152/ajprenal.00468.2018
• Keywords: Urology; Physiology
• Public URL: https://nottingham-repository.worktribe.com/output/1580199
• Publisher URL: https://www.physiology.org/doi/abs/10.1152/ajprenal.00468.2018
• Contract Date: May 8, 2019