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IPSE, a parasite-derived, host immunomodulatory infiltrin protein, alleviates resiniferatoxin-induced bladder pain.

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-based 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 IPSE's analgesic effect. In contrast, IPSE's analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not significantly affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-?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, IPSE's nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.

SUBMITTER: Ishida K

PROVIDER: S-EPMC7756320 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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IPSE, a parasite-derived, host immunomodulatory infiltrin protein, alleviates resiniferatoxin-induced bladder pain.

Ishida Kenji K Mbanefo Evaristus C EC Le Loc L Lamanna Olivia O Pennington Luke F LF Finkel Julia C JC Jardetzky Theodore S TS Falcone Franco H FH Hsieh Michael H MH

Molecular pain 20200101

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 ...[more]

PMID: 33342372

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Project description:BackgroundParasitic infections can increase susceptibility to bacterial co-infections. This may be true for urogenital schistosomiasis and bacterial urinary tract co-infections (UTI). We previously reported that this co-infection is facilitated by S. haematobium eggs triggering interleukin-4 (IL-4) production and sought to dissect the underlying mechanisms. The interleukin-4-inducing principle from Schistosoma mansoni eggs (IPSE) is one of the most abundant schistosome egg-secreted proteins and binds to IgE on the surface of basophils and mast cells to trigger IL-4 release. IPSE can also translocate into host nuclei using a nuclear localization sequence (NLS) to modulate host transcription. We hypothesized that IPSE is the factor responsible for the ability of S. haematobium eggs to worsen UTI pathogenesis.MethodsMice were intravenously administered a single 25 μg dose of recombinant S. haematobium-derived IPSE, an NLS mutant of IPSE or PBS. Following IPSE exposure, mice were serially weighed and organs analyzed by histology to assess for toxicity. Twenty-four hours after IPSE administration, mice were challenged with the uropathogenic E. coli strain UTI89 by urethral catheterization. Bacterial CFU were measured using urine. Bladders were examined histologically for UTI-triggered pathogenesis and by PCR for antimicrobial peptide and pattern recognition receptor expression.ResultsUnexpectedly, IPSE administration did not result in significant differences in urine bacterial CFU. However, IPSE administration did lead to a significant reduction in UTI-induced bladder pathogenesis and the expression of anti-microbial peptides in the bladder. Despite the profound effect of IPSE on UTI-triggered bladder pathogenesis and anti-microbial peptide production, mice did not demonstrate systemic ill effects from IPSE exposure.ConclusionsOur data show that IPSE may play a major role in S. haematobium-associated urinary tract co-infection, albeit in an unexpected fashion. These findings also indicate that IPSE either works in concert with other IL-4-inducing factors to increase susceptibility of S. haematobium-infected hosts to bacterial co-infection or does not contribute to enhancing vulnerability to this co-infection.

Project description:Resiniferatoxin (RTX) is a potent agonist of TRPV1, which possesses unique properties that can be utilized to treat certain modalities of pain. In the present study, systemic intraperitoneal (i.p.) administration of RTX resulted in a significant decrease in acute thermal pain sensitivity, whereas localized intrathecal (i.t.) administration had no effect on acute thermal pain sensitivity. Both i.p. and i.t. administration of RTX prevented TRPV1-induced nocifensive behavior and inflammatory thermal hypersensitivity. There were no alterations in mechanical sensitivity either by i.p. or i.t. administration of RTX. In spinal dorsal horn (L4-L6), TRPV1 and substance P immunoreactivity were abolished following i.p. and i.t. administration of RTX. In dorsal root ganglia (DRG), TRPV1 immunoreactivity was diminished following i.p. administration, but was unaffected following i.t. administration of RTX. Following i.p. administration, basal and evoked calcitonin gene-related peptide release were reduced both in the spinal cord and peripheral tissues. However, following i.t. administration, basal and evoked calcitonin gene-related peptide release were reduced in spinal cord (L4-L6), but were unaffected in peripheral tissues. Both i.p. and i.t. RTX administration lowered the body temperature acutely, but this effect reversed with time. Targeting TRPV1-expressing nerve terminals at the spinal cord can selectively abolish inflammatory thermal hypersensitivity without affecting acute thermal sensitivity and can preserve the efferent functions of DRG neurons at the peripheral nerve terminals. I.t. administration of RTX can be considered as a strategy for treating certain chronic and debilitating pain conditions.Localized administration of RTX in spinal cord could be a useful strategy to treat chronic debilitating pain arising from certain conditions such as cancer and at the same time could maintain normal physiological peripheral efferent functions mediated by TRPV1.

Dataset Information

IPSE, a parasite-derived, host immunomodulatory infiltrin protein, alleviates resiniferatoxin-induced bladder pain.

Publications

IPSE, a parasite-derived, host immunomodulatory infiltrin protein, alleviates resiniferatoxin-induced bladder pain.

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