Toll-like receptor 7 is overexpressed in the bladder of Hunner-type interstitial cystitis, and its activation in the mouse bladder can induce cystitis and bladder pain

Ichihara, Koji; Aizawa, Naoki; Akiyama, Yoshiyuki; Kamei, Jun; Masumori, Naoya; Andersson, Karl‐Erik; Homma, Yukio; Igawa, Yasuhiko

doi:10.1097/j.pain.0000000000000947

Cited by 17 publications

(33 citation statements)

References 33 publications

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“…Bladder pain‐like nociceptive behavior was assessed, as reported in previous studies 8,15 . In brief, after 1‐h adaptation to the measurement cage, the nociceptive behaviors, such as licking or biting of the lower abdominal skin, were recorded for the next 30 min as a baseline.…”

Section: Methodsmentioning

confidence: 99%

“…In brief, under isoflurane anesthesia, decerebration was carried out at the pre‐collicular position. Two hours after stopping anesthesia, CMG measurements were carried out during saline instillation at 10 µL/min, as described in previous studies 8,15 . Stable and reproducible CMG recordings for 60 min were averaged, and basal pressure, threshold pressure, maximum pressure, voided volume, residual volume and intercontraction interval were assessed 16 …”

Section: Methodsmentioning

confidence: 99%

“…The bladder bodies, half of which were divided into the detrusor and mucosal layer, and L6 DRGs of the killed mice were harvested at 24 h after saline or LPS instillation, and conserved in RNA stabilization reagent. Extraction of total RNA, reverse transcription to cDNA and RT–PCR for relative quantification of mRNA expression of the TRP channels expressing in the bladder and L6 DRGs (TRPA1, TRPM2, TRPM7, TRPM8, TRPV1 and TRPV4) were carried out, as described in previous studies 8,13,15 . Table shows the primer sequences.…”

Section: Methodsmentioning

confidence: 99%

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Lacking transient receptor potential melastatin 2 attenuates lipopolysaccharide‐induced bladder inflammation and its associated hypersensitivity in mice

Kamei¹,

Aizawa²,

Nakagawa³

et al. 2020

Int J of Urology

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ObjectiveTo study the role of transient receptor potential melastatin 2 in bladder function and inflammation‐associated hypersensitivity.MethodsWe evaluated physiological function of the bladder and intravesical lipopolysaccharide‐induced inflammatory nociceptive responses in female wild‐type and transient receptor potential melastatin 2‐knockout mice. In vivo frequency/volume and decerebrated unanesthetized cystometry measurements, as well as in vitro detrusor strip functional studies, were carried out to evaluate bladder function. Mice received intravesical lipopolysaccharide (2.0 mg/mL) or saline instillation to evaluate responses to bladder inflammation. Voiding and bladder pain‐like behaviors, cystometry measurements and histological evaluation were carried out before and after intravesical lipopolysaccharide instillation.ResultsFew phenotypic differences in in vivo and in vitro physiological function were found between the two genotypes. Comparison of measurements taken before and 24–48 h after intravesical lipopolysaccharide instillation showed that voiding parameters did not change in transient receptor potential melastatin 2‐knockout mice, whereas an increased voiding frequency was observed in wild‐type mice. At 24 h after intravesical lipopolysaccharide instillation, the numbers of bladder pain‐like behaviors and of infiltrated inflammatory cells in the bladder submucosal layer were significantly increased, and the voided volume and the intercontraction interval were significantly decreased on cystometry measurements in wild‐type mice compared with those in both transient receptor potential melastatin 2‐knockout mice and in wild‐type mice treated with saline instillation.ConclusionsAlthough the physiological roles of transient receptor potential melastatin 2 channels in the bladder might be limited, inflammation and associated hypersensitivity of the bladder caused by intravesical lipopolysaccharide instillation are attenuated in transient receptor potential melastatin 2‐knockout mice, suggesting pathophysiological roles of transient receptor potential melastatin 2 channels in these processes.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Lacking transient receptor potential melastatin 2 attenuates lipopolysaccharide‐induced bladder inflammation and its associated hypersensitivity in mice

Kamei¹,

Aizawa²,

Nakagawa³

et al. 2020

Int J of Urology

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“…Ichihara et al [ 25 ] studied TLR7 expression in bladder biopsy specimens from patients with Hunner-type IC. They also explored the functional roles of TLR7 in bladder inflammation and nociception in mice.…”

Section: Antagonists Of Toll-like Receptorsmentioning

confidence: 99%

“…They also explored the functional roles of TLR7 in bladder inflammation and nociception in mice. Ichihara et al [ 25 ] found that the number of TLR7 immuno-reactive cells and the mRNA expression of TLR7 were significantly higher in IC specimens than in samples from controls without the disease. Loxoribine, a TLR7 agonist, instilled in the bladder of C57BL/6N female mice, induced edema, congestion, and inflammation, and significantly increased the TLR7-mRNA expression.…”

Section: Antagonists Of Toll-like Receptorsmentioning

confidence: 99%

Current Pharmacologic Approaches in Painful Bladder Research: An Update

Andersson

Birder

2017

Int Neurourol J

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The symptoms of interstitial cystitis (IC)/bladder pain syndrome (BPS) may have multiple causes and involve many contributing factors. Traditional treatments (intravesical instillations) have had a primary focus on the bladder as origin of symptoms without adequately considering the potential influence of other local (pelvic) or systemic factors. Systemic pharmacological treatments have had modest success. A contributing factor to the low efficacy is the lack of phenotyping the patients. Individualized treatment based on is desirable, but further phenotype categorization is needed. There seems to be general agreement that IC is a unique disease and that BPS is a syndrome with multiple pathophysiologies, but this has so far not been not been well reflected in preclinical research with the aim of finding new pharmacological treatments. Current research approaches, including anti-nerve growth factor treatment, anti-tumor necrosis factor-α treatment, activation of SHIP1 (AQX-1125), and P2X3 receptor antagonists, and α1-adrenoceptor antagonists are potential systemic treatments, implying that not only the bladder is exposed to the administered drug, which may be beneficial if the IC/BPS is a bladder manifestation of a systemic disease, or negative (adverse effects) if it is a local bladder condition. Local treatment approaches such as the antagonism of Toll-like receptors (which still is only experimental) and intravesical liposomes (with positive proof-of-concept), may have the advantages of a low number of systemic adverse effects, but cannot be expected to have effects on symptoms generated outside the bladder. Assessment of which of the treatment approaches discussed in this review that can be developed into useful therapies requires further studies.

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Long noncoding RNA (MEG3) in urinal exosomes functions as a biomarker for the diagnosis of Hunner‐type interstitial cystitis (HIC)

Liu

Chen

Liu

et al. 2019

J of Cellular Biochemistry

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Background Toll‐like receptor‐7 (TLR7) is functionally involved in the pathogenesis of Hunner‐type interstitial cystitis (HIC). In addition, maternally expressed gene 3 (MEG3) is implicated in many urethral diseases. In this study, we aimed to verify the hypothesis that exosomal MEG3 in urine can be used as a novel diagnostic biomarker for HIC. Methods Electron microscopy was utilized to observe the distribution of urinary exosomes between the case group and the control group. Receiver operating characteristic analysis was utilized to compare the diagnostic values of MEG3 and miR‐19a‐3p. Computational analysis and luciferase assay were conducted to identify the correlation between MEG3 and miR‐19a‐3p as well as between TLR7 and miR‐19a‐3p. In addition, real‐time polymerase chain reaction and Western blot were performed to establish the signaling pathways implicated in the pathogenesis of HIC. Results When age and gender distributions are excluded, urinary exosomes were equally distributed between case and control groups. The area under the curve of MEG3 was larger than that of miR‐19a‐3p, indicating that MEG3 has a better value in the diagnosis of HIC. In addition, patients with HIC showed elevated MEG3 expression and inhibited miR‐19a‐3p expression, thus establishing a negative correlation between MEG3 and miR‐19a‐3p. MEG3 and TLR7 were both identified as targets of miR‐19a‐3p, establishing a MEG3/miR‐19a‐3p/TLR7 signaling pathway, in which MEG3 enhances the expression of TLR7 via inhibiting the expression of miR‐19a‐3p. Conclusion MEG3 level was upregulated in patients with HIC. In addition, MEG3 downregulated miR‐19a‐3p expression while upregulating TLR7 expression. Furthermore, MEG3 contributes to the pathogenesis of HIC. Therefore, exosomal MEG3 in urine can be used as a biomarker for HIC diagnosis.

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Toll-like receptor 7 is overexpressed in the bladder of Hunner-type interstitial cystitis, and its activation in the mouse bladder can induce cystitis and bladder pain

Cited by 17 publications

References 33 publications

Lacking transient receptor potential melastatin 2 attenuates lipopolysaccharide‐induced bladder inflammation and its associated hypersensitivity in mice

Lacking transient receptor potential melastatin 2 attenuates lipopolysaccharide‐induced bladder inflammation and its associated hypersensitivity in mice

Current Pharmacologic Approaches in Painful Bladder Research: An Update

Long noncoding RNA (MEG3) in urinal exosomes functions as a biomarker for the diagnosis of Hunner‐type interstitial cystitis (HIC)

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