Abstract
Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease of the upper airways involving nasal cavity and sinus. Deriving both from its clinical complexity with protean clinical manifestations as well its pathogenetic heterogeneity, the molecular mechanisms contributing to the pathogenesis of CRS remain unclear, and attract a wide interest in the field. Current evidences indicate that IL-17A is highly expressed in chronic rhinosinusitis with nasal polyps (CRSwNP). However, its pathogenetic role in regulation of tissue remodeling of CRSwNP remains unknown. The present study aimed to investigate the cellular origins and functions of IL-17A cytokine in CRSwNP, and further determined whether IL-17A could affect the expression of metalloproteinases (MMPs), the remodeling factors of CRSwNP. The results showed that the expression of IL-17A was upregulated in nasal tissues of patients with CRSwNP compared to those with chronic rhinosinusitis without nasal polyps (CRSsNP) and controls. CD8+ cytotoxic T lymphocytes (Tc) were major IL-17A producers in nasal tissues of CRSwNP. Interleukin (IL)-17-producing CD8+ T cells (Tc17) was significantly higher in nasal tissues of CRSwNP than CRSsNP and controls. Nonetheless, no difference was observed among the IL-17A in peripheral blood lymphocytes of these three groups. Moreover, in the same patients, IL-17A expression was negligible in lymphocytes of peripheral blood when compared with nasal tissues. Increased gene and protein expression of MMP-7 and MMP-9 in patients with CRSwNP compared with controls were observed. In CRSwNP samples, IL-17A receptor (IL-17AR) co-localized with MMP-9 and they were mainly expressed in the epithelial cells. MMP-9 expression was up-regulated both in Primary human nasal epithelial cells (PHNECs) and a nasal epithelial cell line (RPMI 2650) by IL-17A treatment, and diminished by anti-IL-17AR treatment. Furthermore, IL-17A promoted the expression of MMP-9 by activating the NF-κB signal pathway. Thus, our results have revealed a crucial role of IL-17A and Tc cells on pathogenesis and tissue remodeling of CRSwNP.
Highlights
Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease of the upper airways involving nasal cavity and sinus, with an estimated worldwide prevalence of 5–16% [1,2,3]
Tissues obtained from patients with chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and control subjects analyzed for IL-17A expression by ELISA demonstrated that IL-17A protein levels were significantly increased in patients with CRSwNP and CRSsNP compared with controls (P = 0.001, P = 0.012)
The focus of the present study on molecular mechanisms contributing to the pathogenesis of chronic rhinosinusitis (CRS) derives both from its clinical complexity with protean clinical manifestations as well its pathogenetic heterogeneity with involvement of multiple inflammatory factors
Summary
Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease of the upper airways involving nasal cavity and sinus, with an estimated worldwide prevalence of 5–16% [1,2,3]. As defined in the European Position Paper on Rhinosinusitis and Nasal Polyps 2012 (EPOS2012) of the European Rhinologic Society, CRS is currently divided on the basis of distinct tissue remodeling patterns into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP) [4]. In contrast to CRSwNP which is typically characterized by excessive degradation of the extracellular matrix (ECM) and the presence of pseudocyst formations with albumin accumulation and edema formation [5], CRSsNP is defined by excessive extracellular matrix (ECM) deposition and fibrosis formation [6]. Recent studies have suggested that the imbalance between MMPs and their tissue inhibitor of metalloproteinases (TIMPs) is one of the most causes leading to the pathological tissue remodeling seen frequently in CRS [9,10,11]. The detailed upstream regulation of MMPs/TIMPs balance that promotes the tissue remodeling remains largely unclear
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