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bioRxiv · 10.1101/2020.06.11.146829

IPSE, a Parasite-Derived, Host Immunomodulatory Infiltrin Protein, Alleviates Resiniferatoxin-Induced Bladder Pain

Ishida, K.·Mbanefo, E.·Le, L.·Lamanna, O.·Pennington, L.·Finkel, J.·Jardetzky, T.·Falcone, F.·Hsieh, M.
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Abstract

The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-dependent mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSEs analgesic effect. In contrast, IPSEs analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not dramatically affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-{kappa}b-related signaling pathway genes. In vitro testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSEs nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.

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Ishida, K., Mbanefo, E., Le, L., Lamanna, O., Pennington, L., Finkel, J., Jardetzky, T., Falcone, F., Hsieh, M.. 2020-06-12. IPSE, a Parasite-Derived, Host Immunomodulatory Infiltrin Protein, Alleviates Resiniferatoxin-Induced Bladder Pain. https://doi.org/10.1101/2020.06.11.146829

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