Upregulation of Basonuclin1 Is Associated with p63-Involved Epithelial Barrier Impairment and Type-2 Helper T-cell Inflammation in Chronic Rhinosinusitis with Nasal Polyps

Background: Tumor protein p63 has been shown to be important for epithelial dysfunction, including epithelial barrier defects and mucosal inflammation, in the development of chronic rhinosinusitis with nasal polyps (CRSwNP). Basonuclin1 (BNC1), an epithelial-specific transcriptional factor, is a direct downstream target of p63 and thus might be involved in the pathogenesis of CRSwNP. Objective: We sought to investigate whether BNC1 was associated with p63-mediated epithelial barrier defects and nasal mucosal inflammation in CRSwNP. Methods: Nasal tissue biopsies were obtained from 91 patients to CRSwNP, 49 chronic rhinosinusitis without nasal polyps (CRSsNP) patients, and 28 control subjects. Immunohistochemistry and immunofluorescence staining were used to determine the distribution of BNC1 in tissues and localization in cells, respectively. Quantitative PCR was performed to detect the expression levels of BNC1, TP63, epithelial barrier proteins, and type-2 helper T-cell inflammation-related genes. Results: BNC1 mRNA expression was significantly elevated in the tissues in CRSwNP patients compared with CRSsNP (1.96-fold, p = 0.0003) and control groups (2.40-fold, p < 0.0001). BNC1 staining was strongly positive in the nasal epithelium and co-localized with p63-positive epithelial cells. The expression of BNC1 mRNA was strongly correlated with TP63 mRNA level both in tissue biopsies (r = 0.78, p < 0.0001) and epithelial scrapings (r = 0.97, p < 0.0001). BNC1 expression was also positively correlated with epithelial barrier protein genes (CDH1, CLDN1, CLDN4, TJP1, and TJP2) and epithelial genes involved in TH2 inflammation (IL33, CCL26, CLC, and ALOX15). Conclusions: Overexpression of BNC1 may be associated with increased expression of TP63, and possibly contribute to the epithelial barrier defects and TH2 inflammation in CRSwNP.

Download Full-text

γδT cells contribute to type 2 inflammatory profiles in eosinophilic chronic rhinosinusitis with nasal polyps

Clinical Science ◽

10.1042/cs20190481 ◽

2019 ◽

Vol 133 (22) ◽

pp. 2301-2315 ◽

Cited By ~ 1

Author(s):

Xia Li ◽

Zhiyuan Wang ◽

Lihong Chang ◽

Xiaohong Chen ◽

Luoying Yang ◽

...

Keyword(s):

Chronic Rhinosinusitis ◽

Murine Model ◽

Inflammatory Markers ◽

Nasal Polyps ◽

Γδt Cells ◽

Control Subjects ◽

Nasal Tissue ◽

Type 2 Cytokines ◽

Eosinophilic Chronic Rhinosinusitis

Abstract Eosinophilic chronic rhinosinusitis with nasal polyps (ECRS) is a condition linked with type 2 inflammation, poor treatment outcomes, and high recurrence tendency. Although γδT cells have been reported to induce type 2 immune responses and eosinophilic infiltration in several diseases, their role in ECRS has not been fully explored. We aimed to evaluate the association of γδT cells with the type 2 inflammatory profiles in ECRS. Nasal tissue samples obtained from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) (51 eosinophilic and 48 non-eosinophilic), 50 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 58 control subjects were examined for γδT cells, inflammatory markers and eosinophils using HE, RT-qPCR, ELISA, immunofluorescence, and flow cytometry. In parallel, studies were also conducted in an ECRS murine model induced by anti-γδT cells neutralizing antibody administration. γδT cells expression was significantly increased in tissues from patients with ECRS compared with non-ECRS, CRSsNP and control subjects. Moreover, inflammatory markers including type 2 proinflammatory cytokines (IL-4, IL-5, IL-13), GATA3, eosinophil cationic protein (ECP), and eotaxin levels were also increased in nasal tissues of patients with ECRS, and Vγ1+ γδT cells mRNA expression was positively correlated with type 2 cytokines, GATA3, and ECP. In the ECRS murine model, anti-Vγ1+ γδT antibody treatment reduced the infiltration of eosinophils and expression of type 2 cytokines, GATA3, and ECP in nasal mucosae. In conclusion, the results of the present study suggest that γδT cells play a crucial role in the type 2 inflammatory profiles and nasal tissue eosinophilic infiltration in patients with ECRS.

Download Full-text

Increased Expression of TXNIP Facilitates Oxidative Stress in Nasal Epithelial Cells of Patients With Chronic Rhinosinusitis With Nasal Polyps

American Journal of Rhinology and Allergy ◽

10.1177/1945892420982411 ◽

2020 ◽

pp. 194589242098241

Author(s):

Hai Lin ◽

Guangyi Ba ◽

Ru Tang ◽

Mingxian Li ◽

Zhipeng Li ◽

...

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Real Time ◽

Chronic Rhinosinusitis ◽

Western Blotting ◽

Real Time Pcr ◽

Nasal Polyps ◽

Sod Activity ◽

Nasal Tissue ◽

Sod Assay

Background Oxidative stress plays crucial roles in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Thioredoxin-interacting protein (TXNIP) is essential in the process of triggering oxidative stress. However, its role and mechanism in CRSwNP remain unclear. The present study sought to explore the role and mechanism of TXNIP in the pathogenesis of CRSwNP. Methods Western blotting, real-time PCR and immunohistochemistry (IHC) were employed to assess TXNIP, thioredoxin (TRX) expression in nasal tissue samples from patients with CRSwNP and control subjects. MDA level and SOD activity in nasal tissue homogenates were measured using MDA and SOD Assay Kit. To evaluate the role and mechanism of TXNIP in CRSwNP, human nasal epithelial cells (HNECs) were cultured and stimulated using TXNIP siRNA, with or without N-acetylcysteine (NAC, an ROS scavenger). Western blotting, real-time PCR, ROS detecting dye DCFH-DA, MDA and SOD Assay Kit were performed to assess the effects and mechanisms of stimulators on the cells. Results We found significantly increased levels of TXNIP and decreased levels of TRX protein, mRNA, positive cells, increased MDA level and decreased SOD activity in CRSwNP patients compared with control subjects. In vitro study, significantly altered levels of TXNIP, TRX, MDA, SOD and ROS in HNECs were found following treatment of TXNIP siRNA with or without NAC on HNECs. Conclusion TXNIP expression was increased and TRX expression was decreased in CRSwNP at both protein and mRNA levels. MDA levels were increased and SOD activities were decreased in CRSwNP. TXNIP may have negative association with TRX, and then decrease SOD activities and increase MDA levels, resulting in the upregulation of ROS and oxidative stress in HNECs, which may play a pivotal role in the pathogenesis of CRSwNP. Future studies are expected to further explore the role and mechanism of TXNIP in CRSwNP.

Download Full-text

A single antigen-specific B cell can conjugate to either a type 1 or a type 2 helper T cell.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.85.20.7724 ◽

1988 ◽

Vol 85 (20) ◽

pp. 7724-7728 ◽

Cited By ~ 5

Author(s):

V. M. Sanders ◽

R. Fernandez-Botran ◽

R. L. Coffman ◽

T. R. Mosmann ◽

E. S. Vitetta

Keyword(s):

T Cell ◽

B Cell ◽

Helper T Cell ◽

Single Antigen

Download Full-text

Type 2 Helper T-Cell Cytokines Induce Morphologic and Molecular Characteristics of Atopic Dermatitis in Human Skin Equivalent

American Journal Of Pathology ◽

10.1016/j.ajpath.2011.01.037 ◽

2011 ◽

Vol 178 (5) ◽

pp. 2091-2099 ◽

Cited By ~ 34

Author(s):

Marijke Kamsteeg ◽

Mieke Bergers ◽

Roelie de Boer ◽

Patrick L.J.M. Zeeuwen ◽

Stanleyson V. Hato ◽

...

Keyword(s):

Atopic Dermatitis ◽

T Cell ◽

Human Skin ◽

Skin Equivalent ◽

Molecular Characteristics ◽

Helper T Cell ◽

Human Skin Equivalent

Download Full-text

Activation of Activin receptor-like kinases curbs mucosal inflammation and proliferation in chronic rhinosinusitis with nasal polyps

Scientific Reports ◽

10.1038/s41598-018-19955-1 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 2

Author(s):

Lotta Tengroth ◽

Julia Arebro ◽

Olivia Larsson ◽

Claus Bachert ◽

Susanna Kumlien Georén ◽

...

Keyword(s):

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Mucosal Inflammation ◽

Activin Receptor

Download Full-text

Biological therapy of chronic rhinosinusitis

Otorinolaryngologie a foniatrie ◽

10.48095/ccorl2021109 ◽

2021 ◽

Vol 70 (2) ◽

pp. 109-114

Author(s):

Zuzana Balatková ◽

Zdeněk Knížek ◽

Jan Vodička ◽

Jan Plzák

Keyword(s):

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Biological Therapy ◽

Immunoglobulin E ◽

Sinus Surgery ◽

Therapeutic Choice ◽

First Choice ◽

Intranasal Steroids

The aim of this paper is to present an up-to-date information about therapeutical options in chronic rhinosinusitis with nasal polyps. First choice therapy is a long term regular application of intranasal steroids in combination with salinic solution douches. If this treatment is not eff ective enough, then the pulses of systemic steroids are indicated. If the sufficient control of the disease is not achieved, then surgery is a therapeutic choice; it means functional endoscopic sinus surgery in the extent corresponding to the extension of the sinus disease. However, there remains a certain group of patients in whom the results with this treatment are not optimal. The type 2 immunopathological response affects relevantly the course of the disease. Nowadays, the research is done in this field. Specific agents, which are able to block circulating inflammatory mediators or bind receptors for these mediators are developed and studied. The results of the studies having been completed by now are promising. Keywords: biological therapy – chronic rhinosinusitis – nasal polyps – dupilumab – immunoglobulin E – interleukin

Download Full-text

Comparison of Subtyping Approaches and the Underlying Drivers of Microbial Signatures for Chronic Rhinosinusitis

mSphere ◽

10.1128/msphere.00679-18 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 7

Author(s):

Kristi Biswas ◽

Raewyn Cavubati ◽

Shan Gunaratna ◽

Michael Hoggard ◽

Sharon Waldvogel-Thurlow ◽

...

Keyword(s):

Tight Junction ◽

Chronic Rhinosinusitis ◽

Inflammatory Markers ◽

Nasal Polyps ◽

Epithelial Barrier ◽

Clear Understanding ◽

Microbial Composition ◽

Data Set ◽

Heterogeneous Condition ◽

Gene And Protein Expression

ABSTRACT Chronic rhinosinusitis (CRS) is a heterogeneous condition characterized by persistent sinus inflammation and microbial dysbiosis. This study aimed to identify clinically relevant subgroups of CRS patients based on distinct microbial signatures, with a comparison to the commonly used phenotypic subgrouping approach. The underlying drivers of these distinct microbial clusters were also investigated, together with associations with epithelial barrier integrity. Sinus biopsy specimens were collected from CRS patients (n = 23) and disease controls (n = 8). The expression of 42 tight junction genes was evaluated using quantitative PCR together with microbiota analysis and immunohistochemistry for measuring mucosal integrity and inflammation. CRS patients clustered into two distinct microbial subgroups using probabilistic modelling Dirichlet (DC) multinomial mixtures. DC1 exhibited significantly reduced bacterial diversity and increased dispersion and was dominated by Pseudomonas, Haemophilus, and Achromobacter. DC2 had significantly elevated B cells and incidences of nasal polyps and higher numbers of Anaerococcus, Megasphaera, Prevotella, Atopobium, and Propionibacterium. In addition, each DC exhibited distinct tight junction gene and protein expression profiles compared with those of controls. Stratifying CRS patients based on clinical phenotypic subtypes (absence or presence of nasal polyps [CRSsNP or CRSwNP, respectively] or with cystic fibrosis [CRSwCF]) accounted for a larger proportion of the variation in the microbial data set than with DC groupings. However, no significant differences between CRSsNP and CRSwNP cohorts were observed for inflammatory markers, beta-dispersion, and alpha-diversity measures. In conclusion, both approaches used for stratifying CRS patients had benefits and pitfalls, but DC clustering provided greater resolution when studying tight junction impairment. Future studies in CRS should give careful consideration to the patient subtyping approach used. IMPORTANCE Chronic rhinosinusitis (CRS) is a major human health problem that significantly reduces quality of life. While various microbes have been implicated, there is no clear understanding of the role they play in CRS pathogenesis. Another equally important observation made for CRS patients is that the epithelial barrier in the sinonasal cavity is defective. Finding a robust approach to subtype CRS patients would be the first step toward unravelling the pathogenesis of this heterogeneous condition. Previous work has explored stratification based on the clinical presentation of the disease (with or without polyps), inflammatory markers, pathology, or microbial composition. Comparisons between the different stratification approaches used in these studies have not been possible due to the different cohorts, analytical methods, or sample sites used. In this study, two approaches for subtyping CRS patients were compared, and the underlying drivers of the heterogeneity in CRS were also explored.

Download Full-text