Viral stimulation modulates endotype-related ACE2 expression in eosinophilic chronic rhinosinusitis

2021 ◽  
Vol 59 (5) ◽  
pp. 460-469
Author(s):  
S.-N. Hong ◽  
J.K. Kim ◽  
J.-A. Kim ◽  
H. Cha ◽  
J.Y. Kim ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Chronic Rhinosinusitis ◽  
Nasal Mucosa ◽  
Poly I:C ◽  
Tissue Type ◽  
Angiotensin Converting Enzyme 2 ◽  
Polyinosinic:Polycytidylic Acid ◽  
Eosinophilic Chronic Rhinosinusitis ◽  
Induced Changes ◽  
Air Liquid Interface

Background: Angiotensin-converting enzyme 2 (ACE2), a receptor targeted by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the nasal mucosa. Chronic rhinosinusitis (CRS) shows diverse endotypes and is aggravated by viral infection. Whether viral stimulation and CRS endotype influence ACE2 expression remains unclear. We investigated the expression of ACE2 and the transmembrane protease, serine 2 (TMPRSS2), which mediate the entry of SARS-CoV-2 into cells, and assessed polyinosinic:polycytidylic acid (poly[I:C])-induced changes based on CRS endotype. Methodology: ACE2 and TMPRSS2 expression was evaluated based on CRS phenotype, endotype, and tissue type. Correlations between ACE2/TMPRSS2 expression and inflammatory mediators in nasal polyps (NP) were examined. Air-liquid interface culture experiments were performed to assess the effects of major cytokines or poly(I:C) stimulation on ACE2/TMPRSS2 expression in primary epithelial cells from healthy nasal mucosa, eosinophilic NP (ENP), and non-eosinophilic NP (NENP). Results: In primary nasal epithelial cells, interleukin (IL)-13 decreased ACE2 expression but increased TMPRSS2. Eosinophilic CRS showed lower ACE2 expression than non-eosinophilic CRS, regardless of CRS phenotype. CRS endotype was an independent factor associated with ACE2/TMPRSS2 expression in NP. Serum and tissue eosinophilic marker levels were inversely correlated with ACE2 expression, whereas tissue neutrophilic marker levels and ACE2 expression were positively correlated in NP. ACE2 expression was suppressed in ENP tissues; however, a combination of poly(I:C) and IL-13 induced ACE2/TMPRSS2 upregulation in ENP. Conclusions: ENP tissues have lower ACE2 expression than NENP; however, viral stimulation promotes ACE2/TMPRSS2 upregulation in ENP.

Regulation of the Expression of SARS-CoV-2 Receptor Angiotensin-Converting Enzyme 2 in Nasal Mucosa

2021 ◽  
pp. 194589242110277
Author(s):  
Tetsuji Takabayashi ◽  
Kanako Yoshida ◽  
Yoshimasa Imoto ◽  
Robert P. Schleimer ◽  
Shigeharu Fujieda
Keyword(s):  
Epithelial Cells ◽  
Angiotensin Converting Enzyme ◽  
Nasal Mucosa ◽  
Japanese Cedar ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Japanese Cedar Pollen ◽  
Cedar Pollen

Background Coronavirus disease 2019 (COVID-19) has caused a global pandemic. Higher expression of the virus receptor angiotensin-converting enzyme 2 (ACE2) in the nasal mucosa may be associated with high transmissibility and asymptomatic infection. In COVID-19, the elucidation of the determinants of ACE2 expression at nasal tissue level is crucial. The development of strategies to downregulate ACE2 expression in nasal epithelial cells might reduce transmission and be useful as a novel therapeutic approach. Objective To verify ACE2 expression in the nasal mucosa of patients with seasonal allergic rhinitis induced by Japanese cedar pollen (SAR-JCP) and chronic rhinosinusitis with nasal polyp (CRSwNP) and to examine the effects of short-chain fatty acids (SCFAs) on ACE2 expression in airway epithelial cells. Methods We assessed ACE2 expression in the nasal mucosa of control subjects, patients with SAR-JCP, and those with CRSwNP using real-time polymerase chain reaction. We also quantified ACE2 gene expression in cultured airway epithelial cells. Results Although ACE2 expression was greatly increased in a few patients with SAR-JCP during the Japanese cedar pollen season, mean levels were not significantly increased. ACE2 mRNA expression was significantly decreased in nasal polyp tissue from patients with chronic rhinosinusitis compared with the expression in that from control subjects. SCFAs generated by gastrointestinal microbiota significantly reduced resting ACE2 expression in cultured airway epithelial cells. SCFAs also significantly suppressed the dsRNA-dependent upregulation of ACE2 expression in airway epithelial cells. Conclusion Inflammatory endotype affects ACE2 expression in the nasal mucosa and influences susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In particular, type 2 inflammation could downregulate ACE2 expression in the nasal mucosa and reduces susceptibility to SARS-CoV-2 in patients with CRSwNP. Although in vivo experiments are required, administration of SCFAs to the nasal cavity might be worthy of consideration as a preventative or therapeutic strategy for the early-stage COVID-19.

scholarly journals The Expression of ephrinA1/ephA2 Receptor Increases in Chronic Rhinosinusitis and ephrinA1/ephA2 Signaling Affects Rhinovirus-Induced Innate Immunity in Human Sinonasal Epithelial Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Sang Hag Lee ◽  
Sung Hoon Kang ◽  
Mun Soo Han ◽  
Ji Won Kwak ◽  
Hyeon Geun Kim ◽  
...  
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Chronic Rhinosinusitis ◽  
Cultured Cells ◽  
Normal Mucosa ◽  
Poly I:C ◽  
Type I ◽  
Antiviral Immune Response ◽  
Immune Mediators ◽  
Sinonasal Mucosa

EphA2 receptor and its ephrin ligands are involved in virus infection, epithelial permeability, and chemokine secretion. We hypothesized that ephrinA1/ephA2 signaling participates in rhinovirus (RV)-induced antiviral immune response in sinonasal mucosa of patients with chronic rhinosinusitis (CRS). Therefore, we investigated the expression of ephrinA1/ephA2 in normal and inflamed sinonasal mucosa and evaluated whether they regulate chemokine secretion and the production of antiviral immune mediators including interferons (IFNs) in RV-infected human primary sinonasal epithelial cells. For this purpose, the expression and distribution of ephrinA1/ephA2 in sinonasal mucosa were evaluated with RT-qPCR, immunofluorescence, and western blot. Their roles in chemokine secretion and the production of antiviral immune mediators such as type I and III IFNs, and interferon stimulated genes were evaluated by stimulating ephA2 with ephrinA1 and inactivating ephA2 with ephA2 siRNA or inhibitor in cells exposed to RV and poly(I:C). We found that ephrinA1/ephA2 were expressed in normal mucosa and their levels increased in inflamed sinonasal mucosa of CRS patients. RV infection or poly(I:C) treatment induced chemokine secretion which were attenuated by blocking the action of ephA2 with ephA2 siRNA or inhibitor. The production of antiviral immune mediators enhanced by rhinovirus or poly (I:C) is increased by blocking ephA2 compared with that of cells stimulated by either rhinovirus or poly(I:C) alone. In addition, blocking ephA2 attenuated RV replication in cultured cells. Taken together, these results describe a novel role of ephrinA1/ephA2 signaling in antiviral innate immune response in sinonasal epithelium, suggesting their participation in RV-induced development and exacerbations of CRS.

scholarly journals S100A8 Enhances IL-1β Production from Nasal Epithelial Cells in Eosinophilic Chronic Rhinosinusitis

2021 ◽  
Author(s):  
Ayaka Nakatani ◽  
Takeshi Tsuda ◽  
Yohei Maeda ◽  
Masaki Hayama ◽  
Daisuke Okuzaki ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Chronic Rhinosinusitis ◽  
Nasal Polyps ◽  
Expression Profiles ◽  
Allergic Inflammation ◽  
Gene Expression Profiles ◽  
Interleukin 1Β ◽  
Nasal Epithelial Cells ◽  
Human Nasal Epithelial Cells ◽  
Eosinophilic Chronic Rhinosinusitis

Abstract Chronic rhinosinusitis is classified into eosinophilic chronic rhinosinusitis (ECRS) and non-eosinophilic chronic rhinosinusitis (NECRS). ECRS is a refractory allergic disease involving a variety of immune and epithelial cells. S100A8 is a damage-associated molecular pattern that is closely related to allergic inflammation. However, the pathological implications of S100A8 in ECRS have not been clarified. We evaluated the role of S100A8 in the pathogenesis of ECRS. Gene expression profiles of nasal polyps obtained from patients with ECRS or NECRS were evaluated using RNA sequencing. S100A8 was identified as a significantly upregulated gene in nasal polyps associated with ECRS. Immunohistochemistry consistently revealed intense S100A8 staining in nasal polyps from patients with ECRS. Human nasal epithelial cells expressed the receptor for advanced glycation end products and Toll-like receptor 4. Recombinant S100A8 protein induced interleukin-1β secretion in human nasal epithelial cells. Our data demonstrate that S100A8 results in production of interleukin-1β in the nasal epithelium, which may be involved in the pathogenesis of ECRS.

Nicotinic Cholinergic Receptor Expression in the Human Nasal Mucosa

2003 ◽  
Vol 112 (1) ◽  
pp. 77-84 ◽  
Author(s):  
C. Jane H. Keiger ◽  
Kim R. Jones ◽  
L. Douglas Case ◽  
Amelia F. Drake ◽  
Martin Kendal-Reed ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Nasal Spray ◽  
Nasal Mucosa ◽  
Cholinergic Receptor ◽  
Receptor Expression ◽  
Interindividual Variation ◽  
Tissue Type ◽  
Nachr Subunit ◽  
Number Of Patients ◽  
Nicotinic Cholinergic Receptor

Twenty-four nasal mucosa specimens were obtained from the inferior or middle turbinates of 6 normal subjects and 18 patients with chronic sinusitis, inflammatory polyp formation, or sinus allergies. Reverse transcription—polymerase chain reaction analysis was used to identify the non-neuronal nicotinic cholinergic receptor (nAChR) subunits that were expressed in the nasal mucosa. Collectively, transcripts for α (α1, α2, α3, α4, α6, α7) and β (β2, β3, β4) nAChR subunit genes were detected in the respiratory mucosa. The α3, α7, and β2 subunits were expressed in 92%, 88%, and 75% of the subjects, respectively. There was a high degree of interindividual variation in nAChR subunit gene expression among subjects. A significant univariate association was found between tissue type and β4 expression and between gender and β3 expression. These data suggest that cells in the nasal mucosa express the necessary messenger RNAs (mRNAs) for numerous nAChR combinations. Moreover, our identification of nAChR subunit mRNAs in the nasal mucosa extends the findings of other functional studies of nAChRs in nasal epithelial cells and implies that nicotine from tobacco products such as cigarette smoke and nicotine nasal spray may have direct cellular effects on nasal mucosa cells through activation of homogeneous or heterogeneous nAChRs. A significant number of patients receiving nicotine nasal spray have reported nasal irritation, and there are reports of transient irritation of the throat and trachea with the use of smoke-free nicotine cigarettes. These adverse respiratory effects may be due to activation of nAChRs in epithelial cells of the nose and trachea.

Expression of TLR2 and TLR4 Messenger RNA in the Epithelial Cells of the Nasal Airway

2005 ◽  
Vol 19 (3) ◽  
pp. 236-239 ◽  
Author(s):  
Zhen Dong ◽  
Zhanquan Yang ◽  
Chengshuo Wang
Keyword(s):  
Epithelial Cells ◽  
Chronic Rhinosinusitis ◽  
Nasal Mucosa ◽  
Messenger Rna ◽  
Nasal Epithelial Cells ◽  
Tlr4 Mrna ◽  
Human Nasal Epithelial Cells ◽  
Local Host ◽  
Adult Volunteers

Background Epithelium of nasal mucosa is the first line of defense against invading pathogens. This study investigated the expression of Toll-like receptor (TLR) 2 and TLR4 in epithelial cells of nasal mucosa and understood the role of TLRs in the innate immunity of nasal mucosa. Methods Human nasal epithelial cells were obtained by scraping the middle one-third of inferior turbinates from 30 patients with chronic rhinosinusitis and 20 healthy adult volunteers. The epithelial cells are made into smears. In situ hybridization was performed for TLR2 and TLR4 messenger RNA (mRNA). Results TLR2 and TLR4 mRNA were expressed in the nasal epithelial cells. The expression of the two genes was significantly higher in the chronic rhinosinusitis group than in the normal control (TLR2, t = 8.605, p < 0.0005; TLR4, t = 9.050, p < 0.0005). Conclusion This study is the first to establish the presence of both TLR2 and TLR4 mRNA on epithelial cells of nasal mucosa, and their expression can be up-regulated in infectious conditions. These results show that TLR2 and TLR4 may play a important role in local host defense of nasal mucosa.

scholarly journals Release of Type 2 Cytokines by Epithelial Cells of Nasal Polyps

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Monica Boita ◽  
Caterina Bucca ◽  
Giuseppe Riva ◽  
Enrico Heffler ◽  
Giovanni Rolla
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Chronic Rhinosinusitis ◽  
Cell Cultures ◽  
Nasal Polyps ◽  
Dermatophagoides Pteronyssinus ◽  
Poly I:C ◽  
Type 2 Cytokines ◽  
Sinus Mucosa

Background. T2 inflammation of chronic rhinosinusitis with nasal polyps (CRSwNP) may be influenced by epithelial cytokines release (TSLP, IL-25, and IL-33). We investigated the release of TSLP, IL-25, and IL-33 by epithelial CRSwNP cells compared to epithelial sinus mucosa cells of patients with chronic rhinosinusitis without nasal polyps (CRSsNP).Methods. IL-25, IL-33, and TSLP were measured by ELISA in the supernatant of cell cultures derived by CRSwNP (9 patients, 6 atopic) and CRSsNP (7 patients, 2 atopic) in baseline condition and following stimulation withDermatophagoides pteronyssinus(DP),Aspergillus fumigatus(AF), and poly(I:C).Results. CRSwNP epithelial cells released increased levels of IL-25 (from 0.12 ± 0.06 pg/ml to 0.27 ± 0.1 pg/ml,p<0.01) and TSLP (from 0.77 ± 0.5 pg/ml to 2.53 ± 1.17 pg/ml,p<0.001) following poly(I:C) stimulation, while CRSsNP epithelial cells released increased levels of IL-25 and IL-33 following AF and DP stimulation, respectively (IL-25: from 0.18 ± 0.07 pg/ml to 0.51 ± 0.1 pg/ml,p<0.001; IL-33: from 2.57 ± 1.3 pg/ml to 5.7 ± 3.1 pg/ml,p<0.001).Conclusions. CRSwNP epithelial cells release TSLP and IL-25 when stimulated by poly(I:C) but not by DP or AF, suggesting that viral infection may contribute to maintain and amplify the T2 immune response seen in CRSwNP.

scholarly journals Fluticasone Propionate Suppresses Poly(I:C)-Induced ACE2 in Primary Human Nasal Epithelial Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Akira Nakazono ◽  
Yuji Nakamaru ◽  
Mahnaz Ramezanpour ◽  
Takeshi Kondo ◽  
Masashi Watanabe ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Fluticasone Propionate ◽  
Nasal Mucosa ◽  
Fold Change ◽  
Innate Immune ◽  
Cell Entry ◽  
Poly I:C ◽  
Nasal Epithelial Cells ◽  
Tlr Agonists ◽  
Human Nasal Epithelial Cells

BackgroundFrom the first detection in 2019, SARS-CoV-2 infections have spread rapidly worldwide and have been proven to cause an urgent and important health problem. SARS-CoV-2 cell entry depends on two proteins present on the surface of host cells, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). The nasal cavity is thought to be one of the initial sites of infection and a possible reservoir for dissemination within and between individuals. However, it is not known how the expression of these genes is regulated in the nasal mucosa.ObjectiveIn this study, we examined whether the expression of ACE2 and TMPRSS2 is affected by innate immune signals in the nasal mucosa. We also investigated how fluticasone propionate (FP), a corticosteroid used as an intranasal steroid spray, affects the gene expression.MethodsPrimary human nasal epithelial cells (HNECs) were collected from the nasal mucosa and incubated with Toll-like receptor (TLR) agonists and/or fluticasone propionate (FP), followed by quantitative PCR, immunofluorescence, and immunoblot analyses.ResultsAmong the TLR agonists, the TLR3 agonist Poly(I:C) significantly increased ACE2 and TMPRSS2 mRNA expression in HNECs (ACE2 36.212±11.600-fold change, p&lt;0.0001; TMPRSS2 5.598±2.434-fold change, p=0.031). The ACE2 protein level was also increased with Poly(I:C) stimulation (2.884±0.505-fold change, p=0.003). The Poly(I:C)-induced ACE2 expression was suppressed by co-incubation with FP (0.405±0.312-fold change, p=0.044).ConclusionThe activation of innate immune signals via TLR3 promotes the expression of genes related to SARS-CoV2 cell entry in the nasal mucosa, although this expression is suppressed in the presence of FP. Further studies are required to evaluate whether FP suppresses SARS-CoV-2 viral cell entry.

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