Impact of the long-lived plasma cells in patients with chronic rhinosinusitis with nasal polyps

N

Wogonin attenuates nasal polyp formation by inducing eosinophil apoptosis through HIF-1α and survivin suppression

Abstract Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is an inflammatory sinonasal disorder characterized by eosinophilic inflammation and T-helper 2 skewing. Eosinophil accumulation in sinonasal mucosa comprises a major feature of CRSwNP. The study aimed to investigate the effect of the flavone wogonin in nasal polyposis by assessing its ability to induce eosinophil apoptosis in vitro and attenuate eosinophilic CRSwNP in mice. Double immunofluorescence, immunohistochemistry, flow cytometry, and immunoblotting were performed to evaluate hypoxia-inducible factor (HIF)-1α, survivin, and apoptotic markers in the human eosinophilic EoL-1 cell line or sinonasal tissues from patients with CRS with or without NPs. In sinonasal specimens from patients with CRS, HIF-1α and survivin were up-regulated in eosinophils from patients with NPs compared with levels in patients without NPs. Under hypoxia, HIF-1α and survivin expression was up-regulated in EoL-1 cells. Wogonin down-regulated both HIF-1α and survivin in EoL-1 cells. In addition, overexpression of survivin protected EoL-1 cells against apoptosis in response to wogonin. Moreover, wogonin attenuated nasal polyp formation in a murine model. Our findings suggest that wogonin could induce caspase-3 activation by suppressing HIF-1α and survivin expression in EoL-1 cells. Further studies regarding novel therapeutic options for CRSwNP targeting eosinophil apoptosis are needed

Sirtuin 1 attenuates nasal polypogenesis by suppressing epithelial-to-mesenchymal transition

Background: Nasal polyps (NPs) imply a refractory clinical course in patients with chronic rhinosinusitis (CRS). Previously, we showed that hypoxia-inducible factor (HIF) 1 could mediate nasal polypogenesis through epithelial-to-mesenchymal transition (EMT). Sirtuin 1 (SIRT1), a histone deacetylase, reportedly suppresses the transcriptional activity of HIF-1. Thus we hypothesized that SIRT1 attenuates nasal polyposis by inhibiting HIF-1-induced EMT. Objective: We sought to determine the role of SIRT1 in patients with nasal polyposis. Methods: The effects of SIRT1 on nasal polypogenesis were investigated in previously developed murine models. Immunohistochemistry, immunoblotting, and immunoprecipitation were done to evaluate SIRT1, EMT, and hypoxicmarkers in human nasal epithelial cells or sinonasal tissues from the mice and the patients with CRS with or without NPs. Results: SIRT1 transgenic mice had significantly fewer mucosal lesions with epithelial disruption and fewer NPs than wild-type (WT) mice. In addition, resveratrol (a SIRT1 activator) treatment suppressed nasal polypogenesis in WT mice; however, sirtinol (a SIRT1 inhibitor) administration increased the polyp burden in SIRT1 transgenic mice. In sinonasal specimens from patients with CRS, SIRT1 was downregulated in the mucosa from patients with polyps compared with levels seen in patients without polyps. SIRT1 overexpression or activation reversed hypoxia-induced EMT in human nasal epithelial cells. The intranasal transfection of a small hairpin SIRT1 lentiviral vector induced more nasal polypoid lesions in SIRT1 transgenic mice. Finally, mucosal extracts from patients with CRS without NPs increased SIRT1 expression in nasal epithelial cells, whereas those from patients with CRS with NPs did not. Conclusion: SIRT1 suppressed NP formation, possibly because of inhibition of HIF-1-induced EMT. Thus nasal epithelium SIRT1 might be a therapeutic target for NPs

Superantigen-related TH2 CD4+ T cells in nonasthmatic chronic rhinosinusitis with nasal polyps

Background: Staphylococcus aureus enterotoxin (SAE) superantigens are detected in nasal polyps (NPs), and SAE-specific IgE predicts asthma comorbidity in patients with NPs. However, roles of SAE superantigens and superantigen-related T-cell responses remain to be elucidated in nonasthmatic patients. Objective: We investigated the presence of SAEs and SAE-related T-cell receptor (TCR) V beta (TCRV beta) in nonasthmatic NPs, the phenotypes and functions of SAE-related T cells, and the clinical implication of SAE-related T-cell expansion. Methods: Sinonasal tissue samples were obtained from patients with nonasthmatic chronic rhinosinusitis (CRS) with NPs (CRSwNP), patients with CRS without NPs (CRSsNP), and control subjects. SAE genes were detected by PCR, and the TCRV beta distribution and T-cell phenotypes were examined by flow cytometry. Results: Various SAE genes were detected not only in NPs but also in sinonasal mucosa from patients with CRSsNP and from controls. The S aureus enterotoxin I (SEI) gene was detected in all NPs. The fraction of SEI-responsive TCRV beta(+) (TCRV beta 1(+) and V beta 5.1(+)) CD4(+) T cells was significantly increased only in NPs and the ethmoidal mucosa of patients with CRSwNP, indicating superantigen-induced expansion. The expanded TCRV beta 5.1(+) CD4(+) T cells expressed proliferation marker Ki-67 and the T(H)2 transcription factor GATA3. Furthermore, TCRV beta 5.1(+) CD4(+) T cells in NPs highly expressed T(H)2 markers, including IL-17RB, thymic stromal lymphoprotein receptor, and chemoattractant receptor-homologous molecule expressed on T(H)2 cells, with a potent T(H)2 cytokine-producing ability. Moreover, the expansion of TCRV beta 1(+) or V beta 5.1(+) CD4(+) T cells was associated with the Lund-Mackay computed tomography score, indicating disease extent. Conclusion: In nonasthmatic patients with CRSwNP, superantigen-related expansion of CD4(+) T cells with T(H)2 differentiation was associated with the disease extent.Y

Bone morphogenetic protein-2 as a novel biomarker for refractory chronic rhinosinusitis with nasal polyps

Background: Bone morphogenetic proteins (BMPs), which are members of the TGF-beta superfamily, regulate bone remodeling by stimulating osteoblasts and osteoclasts. Although the association between osteitis and poor surgical outcomes is well known in patients with chronic rhinosinusitis (CRS), BMPs have not been fully investigated as potential biomarkers for the prognosis of CRS. Objective: Our aim was to investigate the role of BMPs in osteitis in patients with CRS with nasal polyps (NPs) (CRSwNPs), as well as associations between BMPs and inflammatory markers in sinonasal tissues from patients with CRSwNP. Methods: We investigated the expression of 6 BMPs (BMP-2, BMP-4, BMP-6, BMP-7, BMP-9, and BMP-10) and their cellular origins in NPs of human subjects by using immunohistochemistry and ELISA of NP tissues. Exploratory factor analysis was performed to identify associations between BMPs and inflammatory markers. Air-liquid interface cell culture of human nasal epithelial cells was performed to evaluate the induction of the epithelial-mesenchymal transition by BMPs. Results: Of the 6 BMPs studied, BMP-2 and BMP-7 were associated with refractoriness. Only BMP-2 concentrations were higher in patients with severe osteitis and advanced disease extent according to the computed tomography findings. Eosinophils and some macrophages were identified as cellular sources of BMP-2 in immunofluorescence analysis. An in vitro experiment revealed that BMP-2 induced epithelialmesenchymal transition in air-liquid interface-cultured human nasal epithelial cells, particularly in a T(H)2 milieu. Conclusion: BMP-2 could reflect the pathophysiology of mucosa and bone remodeling and may be a novel biomarker for refractory CRSwNP.N