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      Neuroinflammatory gene expression analysis reveals potential novel mediators and treatment targets in interstitial cystitis with Hunner lesions

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          Abstract

          Background

          We sought to study differential neuroinflammatory gene expression in men with interstitial cystitis (IC) with Hunner lesions compared with asymptomatic controls using NanoString, which uses barcoded probes to measure hundreds of genes. IC is a heterogenous condition lacking reliable biomarkers, and a subset of patients exhibits Hunner lesions, implicating the bladder as an inflammatory pain generator.

          Methods

          Blood, urine, and bladder biopsies were collected from 6 men with IC and Hunner lesions. 7 asymptomatic controls had blood and urine collected and 2 benign bladder biopsies were obtained from our tissue bank. RNA was isolated and analyzed with NanoString Human Neuroinflammation panel. Gene expression was considered significant if there was a >1.5-fold change and adjusted P value <0.05 compared with controls.

          Results

          Mean patient age was 61.5 years with 8 years median symptom duration. In bladder tissue, while many cytokine and chemokine genes had higher expression as expected (e.g., TNF, CXCL10), other significant genes included TRPA1 (1098-fold increased, expressed in pain sensing neurons) and TNFRSF17 (735-fold, B-cell related). In urine, there was 114-fold increase in S1PR4, which mediates pain via TRP-dependent pathways. A patient on cyclosporine had lower inflammatory gene expression levels relative to other IC patients, but no difference in TRPA1.

          Conclusions

          Men with IC and Hunner lesions have a diverse set of neuroinflammatory genes with differential expression compared to controls. We identified genes linked to neuropathic pain through the TRP pathway and this expression was not reduced by cyclosporine. These findings open a new direction for biomarker and therapeutic discovery.

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          Most cited references36

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          Direct multiplexed measurement of gene expression with color-coded probe pairs.

          We describe a technology, the NanoString nCounter gene expression system, which captures and counts individual mRNA transcripts. Advantages over existing platforms include direct measurement of mRNA expression levels without enzymatic reactions or bias, sensitivity coupled with high multiplex capability, and digital readout. Experiments performed on 509 human genes yielded a replicate correlation coefficient of 0.999, a detection limit between 0.1 fM and 0.5 fM, and a linear dynamic range of over 500-fold. Comparison of the NanoString nCounter gene expression system with microarrays and TaqMan PCR demonstrated that the nCounter system is more sensitive than microarrays and similar in sensitivity to real-time PCR. Finally, a comparison of transcript levels for 21 genes across seven samples measured by the nCounter system and SYBR Green real-time PCR demonstrated similar patterns of gene expression at all transcript levels.
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            TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.

            TRPA1 is an excitatory ion channel targeted by pungent irritants from mustard and garlic. TRPA1 has been proposed to function in diverse sensory processes, including thermal (cold) nociception, hearing, and inflammatory pain. Using TRPA1-deficient mice, we now show that this channel is the sole target through which mustard oil and garlic activate primary afferent nociceptors to produce inflammatory pain. TRPA1 is also targeted by environmental irritants, such as acrolein, that account for toxic and inflammatory actions of tear gas, vehicle exhaust, and metabolic byproducts of chemotherapeutic agents. TRPA1-deficient mice display normal cold sensitivity and unimpaired auditory function, suggesting that this channel is not required for the initial detection of noxious cold or sound. However, TRPA1-deficient mice exhibit pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity. Thus, TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain.
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              Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment.

              The purpose of this amendment is to provide an updated clinical framework for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome based upon data received since the publication of original guideline in 2011.
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                Author and article information

                Journal
                Transl Androl Urol
                Transl Androl Urol
                TAU
                Translational Andrology and Urology
                AME Publishing Company
                2223-4683
                2223-4691
                November 2021
                November 2021
                : 10
                : 11
                : 4100-4109
                Affiliations
                [1 ]deptDepartment of Urology, Glickman Urological and Kidney Institute , Cleveland Clinic Foundation , Cleveland, OH, USA;
                [2 ]deptDepartment of Immunology, Lerner Research Institute , Cleveland Clinic Foundation , Cleveland, OH, USA
                Author notes

                Contributions: (I) Conception and design: DA Shoskes; (II) Administrative support: P Gotwald; (III) Provision of study materials or patients: DA Shoskes, J Doolittle, BH Lee, KS Keslar, SC Vij; (IV) Collection and assembly of data: DA Shoskes, GT Werneburg, KS Keslar; (V) Data analysis and interpretation: DA Shoskes, GT Werneburg; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

                Correspondence to: Glenn T. Werneburg, MD, PhD. Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Q10-1, Cleveland, OH 44195, USA. Email: wernebg@ 123456ccf.org .
                [^]

                ORCID: 0000-0002-9518-672X.

                Article
                tau-10-11-4100
                10.21037/tau-21-657
                8661250
                34984176
                8432bc97-57ae-42ae-9db4-1408c30a0ac9
                2021 Translational Andrology and Urology. All rights reserved.

                Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

                History
                : 27 July 2021
                : 09 September 2021
                Categories
                Original Article

                interstitial cystitis (ic),lower urinary tract symptoms (luts),bladder pain syndrome,biomarkers,hunner lesions

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