Two-stage genome-wide association study of chronic rhinosinusitis and disease subphenotypes highlights mucosal immunity contributing to risk.
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ABSTRACT:
SUBMITTER: Soliai M
PROVIDER: S-EPMC8048969 | biostudies-literature | 2021 Apr
REPOSITORIES: biostudies-literature
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Two-stage genome-wide association study of chronic rhinosinusitis and disease subphenotypes highlights mucosal immunity contributing to risk.
Soliai Marcus M Sundaresan Agnes S AS Morin Andréanne A Hirsch Annemarie G AG Stanhope Catherine C Kuiper Jordan J Schwartz Brian S BS Ober Carole C Pinto Jayant M JM
International forum of allergy & rhinology 20210103 4
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Project description:BackgroundChronic rhinosinusitis is a multifactorial process disease in which bacterial infection or colonization may play an important role in the initiation or persistence of inflammatory response. The association between mucosal bacteria presence and inflammatory patterns has only been partially explored.ObjectiveTo demonstrate specific mucosal microorganisms possible association with inflammatory patterns.MethodsWe collected nasal polyps or sinus tissues from a clinical selection of six patient groups with defined sinus disease using tissue biomarkers. In the tissues, we detected bacteria using peptide nucleic acid fluorescence in situ hybridization (PNA-FISH).ResultsAfter reviewing a total of 115 samples (15-20 samples per group), the mucosal presence of Staphylococcus aureus was correlated with IL-5 and SE-IgE positive chronic rhinosinusitis with nasal polyps and nasal polyps from cystic fibrosis patients. Chronic rhinosinusitis without nasal polyps with TNFα >20 pg/ml was associated with the mucosal presence of Pseudomonas aeruginosa.ConclusionThis study identifies the relationship between intramucosal microbes and inflammatory patterns, suggesting that bacteria may affect the type of inflammation in chronic rhinosinusitis. Additional investigation is needed to further identify the nature of the relationship.
| S-EPMC4537217 | biostudies-literature
Project description:BackgroundPrior research has identified several components of the innate immune system that may play a significant role in chronic rhinosinusitis (CRS), but the role of innate immunity in patients with CRS is poorly understood. The objective of this study was to determine differential expression of innate immunity genes in the mucosa of patients with CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP) when compared with controls.MethodsControl patients (n = 9) and patients with CRS (n = 36) who failed medical management were prospectively enrolled. Ethmoid mucosa samples were harvested during surgery and quantitative real-time polymerase chain reaction was used to determine levels of mRNA expression of Toll-like receptor (TLR) 2 and TLR9 and interleukin-22 receptor (IL-22R). The average change in crossover threshold and fold change were calculated and differences between controls, CRSwNP, and CRSsNP were compared. Statistical analysis was performed using the Kruskall-Wallis and adjusted Mann-Whitney U tests.ResultsPatients with CRSwNP (n = 16) and CRSsNP (n = 20) showed lower mean expression of TLR2 (p < 0.05) compared with controls. Patients with CRSsNP showed significantly higher mean expression of IL-22R (p < 0.05) than controls.ConclusionThe sinonasal innate immune system may have a significant role in the development of CRS. We found differential expression of innate immune mediators between patients with and without nasal polyposis. These results provide further evidence of disruption of innate immunity at the mucosal level in CRS and highlight differences between polyp- and non-polyp-forming CRS phenotypes at the molecular level. In addition to our knowledge, this is the first report of altered IL-22R expression in CRSsNP patients. This study was a part of the clinical trial NCT01332136 registered in www.clinicaltrials.gov.
| S-EPMC4151703 | biostudies-literature
Project description:PurposeThe 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.MethodsThe 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.ResultsIFN-α and IFN-β 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-1β, tumor necrosis factor-α, 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-α/β/the protein levels of anti-dsDNA IgG.ConclusionsChloroquine may be used for the treatment of patients with eosinophilic CRS.
| S-EPMC7492509 | biostudies-literature
Project description:Bacterial microbiota of the sinuses in CRS.
| PRJEB20232 | ENA
Project description:BackgroundPrevious investigations have provided limited insight into the role of oxidative stress in nasal mucosa inflammation. The aim of this study was to investigate the mechanism of oxidative stress in the epithelial cells of chronic rhinosinusitis with nasal polyps CRSwNP utilizing single-cell RNA sequencing data.MethodsSingle-cell RNA sequencing data from HRA000772 were used to assess oxidative stress, inflammasome activation, and nicotinamide adenine dinucleotide phosphate oxidases (NOXs) expression in epithelial cells via integrative rank-based gene set enrichment analysis. The localization of reactive oxygen species (ROS) and NOX2 in nasal mucosa and cell models was visualized using fluorescent probes and immunohistochemistry, respectively. Functional studies on NOX2 involved siRNA and plasmid transfections in vitro, while Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity was examined using the inducer TMAO and the inhibitor MCC950.ResultsSingle-cell RNA sequencing data suggested an increase of oxidative stress score and NLRP3 inflammasome score in CRSwNP epithelial cells. Vitro experiments demonstrated that lipopolysaccharide could induce ROS accumulation, NLRP3 inflammasome activation and epithelial alarmin expression. MCC950 inhibited the expression of epithelia alarmin in vitro. Elevated NOX2 in CRSwNP epithelial cells was associated with increased ROS, NLRP3 inflammasome activation, and epithelial alarmin expression. NOX2-targeted siRNA inhibited these effects in vitro. Moreover, TMAO reversed the downregulation of epithelial alarmins without impacting ROS levels.ConclusionThis study highlights the crucial role of NOX2 as a key regulator of ROS accumulation and NLRP3 inflammasome activation in CRSwNP, underscoring its potential as a valuable therapeutic target for CRSwNP.
| S-EPMC11425172 | biostudies-literature
Project description:BackgroundChronic rhinosinusitis (CRS) is often differentiated by histopathologic phenotypes (eosinophilic versus neutrophilic), which may impact disease severity measures and outcomes. As such, it has been suggested that counts of cellular elements be included as part of a standard pathological report following endoscopic sinus surgery (ESS).ObjectivesThis cross-sectional study evaluated associations of mucosal eosinophilia and neutrophilia with measures of quality-of-life (QoL) and olfactory function.MethodsPatients with medically refractory CRS completed the SNOT-22 survey and Brief Smell Identification Test (BSIT) at enrollment. In addition, baseline Lund-Mackay computed tomography (CT) and Lund-Kennedy endoscopy scores were collected. Ethmoid mucosa was biopsied during ESS and reviewed using microscopy to quantify densest infiltrate of eosinophils or neutrophils per high-powered-field (HPF). Eosinophilic CRS (eCRS) and neutrophilic CRS (nCRS), both with and without nasal polyposis (NP), were compared across SNOT-22 and BSIT scores.Results77/168 patients demonstrated mucosal eosinophilia (eCRS) while a total of 42/168 patients demonstrated mucosal neutrophilia (nCRS). After adjusting for polyp status, 35/168 had eCRSsNP, 42/168 eCRSwNP, 75/168 non-eCRSsNP, 16/168 non-eCRSwNP. Additionally, 22/161 were noted to have nCRSsNP, 20/161 nCRSwNP, 84/161 non-nCRSwNP, and 35/161 non-nCRSsNP. A small subset of patients demonstrated both eosinophilia and neutrophilia: 14 CRSwNP and 7 CRSsNP. When evaluating average Lund-Mackay Scores (LMS), significant differences existed between non-eCRSsNP and eCRSsNP (p = 0.006). However, after controlling for nasal polyps, eosinophilia did not significantly associate with differences in the Lund-Kennedy Score. Neutrophilia did not significantly associate with any changes in LMS or LKS after controlling for NP. Eosinophilic and neutrophilic histopathologic subtypes did not significantly associate with differences in baseline SNOT-22 or BSIT measures after controlling for NP.ConclusionNeither the presence of mucosal eosinophilia nor mucosal neutrophilia demonstrated significant associations with SNOT-22 quality-of-life or BSIT olfactory function scores when controlling for comorbid nasal polyposis.
| S-EPMC8822192 | biostudies-literature
Project description:Background: Recent studies have implied a role for Th17 cells in CRS with nasal polyps (CRSwNP) patients. However, the capacity of these cells to produce Th17 cytokines is still unknown. Here we sought to quantify IL-17A, IL-17F, IL-21, and IL-22 cytokines produced by Th17 cells in mucosal tissue and peripheral blood of CRSwNP, CRS without nasal polyps (CRSsNP) and control patients. Methods: Samples were prospectively collected from CRS patients and non-CRS controls. We used flow cytometry to characterize the Th17 cells and their cytokines in sinonasal tissue and peripheral blood. Results: A total of 36 patients were recruited to the study. CRSwNP patients had significantly more tissue IL-17A (9.53 ± 2.71 vs. 1.11 ± 0.43 vs. 0.77 ± 0.07), IL-17F (4.96 ± 1.48 vs. 0.88 ± 0.31 vs. 0.56 ± 0.04), IL-21 (5.55 ± 2.01 vs. 1.60 ± 0.71 vs. 1.53 ± 0.55) and IL-22 (4.73 ± 1.58 vs. 0.70 ± 0.28 vs. 0.88 ± 0.26) producing Th17 cells compared to CRSsNP and control mucosa per mg of tissue, respectively. Allergic CRSwNP patients had decreased numbers of IL-21 producing Th17 cells compared to non-Allergic CRSwNP. (1.69 ± 0.57 vs. 9.41 ± 3.23) per mg of tissue, respectively (Kruskal-Wallis p < 0.05). Conclusion: In summary our study identified increased numbers of IL-17A, IL-17F, IL-21 and IL-22 positive Th17 cells in CRSwNP patient polyps and peripheral blood suggesting an altered activation state of those cells both locally and systemically. Atopic CRSwNP had decreased amounts of tissue Th17 cell derived IL-21 implying a potential protective role for IL-21 in CRSwNP allergic inflammation.
| S-EPMC5742278 | biostudies-literature
Project description:The long pentraxin 3 (PTX3) is a prototypic molecule for recognizing pathogens. Liver X receptors (LXRs), belonging to nuclear receptors (NRs) for cholesterol metabolism through heterodimerizing with other NRs, were recently reported to participate in inflammation. However, their roles in chronic rhinosinusitis without nasal polyps (CRSsNP) are unclear. Therefore, this study was sought to explore roles of LXRs in chronic rhinosinusitis (CRS) sinonasal tissues and derived fibroblasts. Immunohistochemistry indicated that LXRα and β expression and lipid/fat deposition were differentially expressed in the control and CRSsNP nasal mucosa. GW7647 (a peroxisome proliferator activated receptor α (PPARα) agonist) and GW3965 (a dual agonist for LXRα and β) significantly caused PTX3 induction in the fibroblast cells. GW3965 induced PTX3 mRNA and protein expression, and the induction substantially led to PTX3 secretion. Meanwhile, an endogenous agonist-cholesterol had a similar enhancing effect on the induction of PTX3 protein. LXR siRNA knockdown to lower LXRα or β expression significantly compromised PTX3 induction. Interestingly, GW3965 also induced phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) activation and its inhibition reduced PTX3 expression. Collectively, we demonstrated here for the first time that CRSsNP nasal mucosa differentially expresses LXRα and β and deposits lipids/fats that may contain cholesterol metabolites to activate LXRs. Activation of LXRs leads to PTX3 production in sinonasal mucosa-derived fibroblasts. Our previous study showed PTX3 overexpression in the nasal cavity of CRSsNP, whereas this study highlights that cholesterol metabolites and LXR activation regulate PTX3 production and may contribute to antimicrobial activity and tissue repair during CRSsNP progression.
| S-EPMC7865759 | biostudies-literature
Project description:Increasing evidence suggests that CRS is a heterogeneous group of sinus disorders involving overlapping but distinct disease entities.The factors leading to different CRS phenotypes remain enigmatic. The role of miRNAs in the regulation of immunological and inflammatory processes is beginning to emerge.Thus, we examined microRNAs expression profiles in eosinophilic CRSwNP adn CRSsNP. Compared with controls, 31 differentially expressed miRNAs (30 downregulated and 1 upregulated miRNAs) in eosinophilic CRSwNP and 4 differentially expressed miRNAs (2 downregulated and 2 upregulated miRNAs) in CRSsNP were indentified. Real time RT-PCR was subsequently performed to verify the miRNA microarray result.
2011-12-08 | GSE32300 | GEO
Project description:Chronic rhinosinusitis (CRS) is a public health problem that has a significant socio-economic impact. Moreover, the complexity of this disease due to its heterogeneous nature based on the underlying pathophysiology - leading to different disease variants - further complicates our understanding and directions for the most appropriate targeted treatment strategies. Several International/national guidelines/position papers and/or consensus documents are available that present the current knowledge and treatment strategies for CRS. Yet there are many challenges to the management of CRS especially in the case of the more severe and refractory forms of disease. Therefore, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), a collaboration between EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus (ICON) on Chronic Rhinosinusitis. The purpose of this ICON on CRS is to highlight the key common messages from the existing guidelines, the differences in recommendations as well as the gaps in our current knowledge of CRS, thus providing a concise reference. In this document we discuss the definition of the disease, its relevance, pharmacoeconomics, pathophysiology, phenotypes and endotypes, genetics and risk factors, natural history and co-morbidities as well as clinical manifestations and treatment options in both adults and children comprising pharmacotherapy, surgical interventions and more recent biological approaches. Finally, we have also highlighted the unmet needs that wait to be addressed through future research.
| S-EPMC4213581 | biostudies-literature