Dataset Information

Chloroquine Treatment Suppresses Mucosal Inflammation in a Mouse Model of Eosinophilic Chronic Rhinosinusitis.

ABSTRACT: PURPOSE:The Toll-like receptor 9 (TLR9) signaling pathway is involved in the pathogenesis of chronic rhinosinusitis (CRS) with nasal polyposis. The aim of this study was to assess the therapeutic potential of the TLR9 pathway inhibitor chloroquine in CRS mice. METHODS:The expression of type I interferons (IFNs) in human CRS tissues was evaluated using quantitative polymerase chain reaction (qPCR), western blotting, and immunofluorescence. Mice were divided into 4 treatment groups: the control, nasal polyp (NP), chloroquine treatment (NP + Chlq), and dexamethasone treatment (NP + Dexa) groups. The effects of chloroquine on polyp formation and mucosal inflammation were examined by hematoxylin and eosin staining. The expression levels of type I IFN, B-cell activating factor (BAFF), TLR9, high mobility group box 1 (HMGB1), and proinflammatory cytokine expression levels were assessed using qPCR, western blot, or enzyme-linked immunosorbent assay. RESULTS:IFN-? and IFN-? mRNA levels were significantly higher in patients with eosinophilic NPs (EPs) than in healthy individuals or non-EP patients. The polyp score, epithelial thickness, mucosal thickness, and the number of eosinophils in nasal mucosa were significantly higher in the NP group compared with the control, NP + Chlq, and NP + Dexa groups. NP + Chlq or NP + Dexa significantly suppressed the induction of type I IFN and BAFF expression in the NP group; these treatments also significantly suppressed the induction of TLR9, HMGB1, interferon regulatory factors, interleukin (IL)-6, IL-1?, tumor necrosis factor-?, and Th cytokine expression in the NP group. The secreted levels of anti-dsDNA Immunoglobulin G (IgG) were significantly higher in the NP group than in the control, NP + Chlq, and NP + Dexa groups. There were significant positive correlations between BAFF and mRNA levels of IFN-?/?/the protein levels of anti-dsDNA IgG. CONCLUSIONS:Chloroquine may be used for the treatment of patients with eosinophilic CRS.

SUBMITTER: Choi MR

PROVIDER: S-EPMC7492509 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Chloroquine Treatment Suppresses Mucosal Inflammation in a Mouse Model of Eosinophilic Chronic Rhinosinusitis.

Choi Mi Ra MR Xu Jun J Lee Seulgi S Yeon Sun Hee SH Park Soo Kyoung SK Rha Ki Sang KS Kim Yong Min YM

Allergy, asthma & immunology research 20201101 6

<h4>Purpose</h4>The Toll-like receptor 9 (TLR9) signaling pathway is involved in the pathogenesis of chronic rhinosinusitis (CRS) with nasal polyposis. The aim of this study was to assess the therapeutic potential of the TLR9 pathway inhibitor chloroquine in CRS mice.<h4>Methods</h4>The expression of type I interferons (IFNs) in human CRS tissues was evaluated using quantitative polymerase chain reaction (qPCR), western blotting, and immunofluorescence. Mice were divided into 4 treatment groups: ...[more]

PMID: 32935491

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Project description:BackgroundEicosanoid receptors are G-protein-coupled receptors playing an important immunomodulatory role in airway diseases. However, there is little information on the expression of these receptors and their link with eosinophilic inflammation in paranasal sinus diseases. We aimed with this study to investigate the tissue expression of leukotrienes and prostaglandin E2 receptors in chronic rhinosinusitis patients and the link of this regulation with eosinophilic inflammation.MethodsSamples were prepared from nasal tissue of patients with chronic rhinosinusitis without nasal polyps (CRS, n = 11), with nasal polyps (CRS-NP, n = 13) and healthy subjects (Controls, n = 6). mRNA expression of CysLT1, CysLT2, BLT1, BLT2, E-prostanoid receptors (EP1, EP2, EP3, EP4) and sol-IL-5Ralpha was determined by real-time PCR. Concentrations of PGE2, LTC4/D4/E4, LTB4 and sol-IL-5Ralpha were determined by ELISA and of ECP by ImmunoCap. Protein expression and tissue localization of eicosanoid receptors and activated eosinophils were evaluated by immunohistochemistry.ResultsCysLT1 mRNA expression was significantly increased in CRS-NP compared to CRS and controls, and CRS compared to controls, whereas CysLT2 mRNA was enhanced in both CRS groups without differences between them. Levels of both receptors correlated to the number of activated eosinophils, sol-IL-5Ralpha, ECP and LTC4/D4/E4 concentrations in the disease groups. PGE2 protein concentrations and prostanoid receptors EP1 and EP3 were down-regulated in the CRS-NP tissue vs. CRS and controls, whereas EP2 and EP4 expression was enhanced in CRS and CRS-NP patients vs. controls. No differences in BLT receptors were observed between patients and controls.ConclusionCyLTs receptors are up-regulated in nasal polyp tissue and their expression correlate with eosinophilic inflammation supporting previous results. Eicosanoid receptors mRNA pattern observed suggests that down-regulation of EP1 and EP3 in CRS-NP and up-regulation EP2 and EP4 in CRS and CRS-NP groups may have some role in the development of the diseases and their regulation may not be directly linked to eosinophil activation but involve post-transcriptional events mainly related to other inflammatory cell sources.

Project description:PURPOSE:Osteitis refers to the development of new bone formation and remodeling of bone in chronic rhinosinusitis (CRS) patients; it is typically associated with eosinophilia, nasal polyps (NPs), and recalcitrant CRS. However, the roles of ossification in CRS with or without NPs remain unclear due to the lack of appropriate animal models. Thus, it is necessary to have a suitable animal model for greater advances in the understanding of CRS pathogenesis. METHODS:BALB/c mice were administered ovalbumin (OVA) and staphylococcal enterotoxin B (SEB). The numbers of osteoclasts and osteoblasts and bony changes were assessed. Micro computed tomography (micro-CT) scans were conducted to measure bone thickness. Immunofluorescence, immunohistochemistry, and quantitative polymerase chain reaction were performed to evaluate runt-related transcription factor 2 (RUNX2), osteonectin, interleukin (IL)-13, and RUNX2 downstream gene expression. Gene set enrichment analysis was performed in mucosal tissues from control and CRS patients. The effect of resveratrol was evaluated in terms of osteogenesis in a murine eosinophilic CRS NP model. RESULTS:The histopathologic changes showed markedly thickened bones with significant increase in osteoblast numbers in OVA/SEB-treated mice compared to the phosphate-buffered saline-treated mice. The structural changes in bone on micro-CT were consistent with the histopathological features. The expression of RUNX2 and IL-13 was increased by the administration of OVA/SEB and showed a positive correlation. RUNX2 expression mainly co-localized with osteoblasts. Bioinformatic analysis using human CRS transcriptome revealed that IL-13-induced bony changes via RUNX2. Treatment with resveratrol, a candidate drug against osteitis, diminished the expression of IL-13 and RUNX2, and the number of osteoblasts in OVA/SEB-treated mice. CONCLUSIONS:In the present study, we found the histopathological and radiographic evidence of osteogenesis using a previously established murine eosinophilic CRS NP model. This animal model could provide new insights into the pathophysiology of neo-osteogenesis and provide a basis for developing new therapeutics.

Dataset Information

Chloroquine Treatment Suppresses Mucosal Inflammation in a Mouse Model of Eosinophilic Chronic Rhinosinusitis.

Publications

Chloroquine Treatment Suppresses Mucosal Inflammation in a Mouse Model of Eosinophilic Chronic Rhinosinusitis.

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