Age-Related Increased Prevalence of Asthma and Nasal Polyps in Chronic Rhinosinusitis and Its Association with Altered IL-6 Trans-Signaling

Abstract

We report that S100 proteins were reduced in patients with chronic rhinosinusitis (CRS). S100A8/9, which is important in epithelial barrier function, was particularly decreased in elderly patients with CRS. Epithelial expression of S100A8/9 is partly regulated by the IL-6 trans-signaling pathway. The goal of this study was to investigate whether or not age-related reduction of S100A8/9 in CRS is associated with blunting of IL-6 trans-signaling. The levels of IL-6, soluble IL-6 receptor (sIL-6R), soluble gp130 (sgp130), and S100A8/9 from control subjects (n = 10), and patients with CRS without nasal polyps (n = 13) and those with CRS with nasal polyps (CRSwNP) (n = 14), were measured by ELISA. Age-related differences in the level of each protein were investigated. Normal human bronchial epithelial cells were cultured in air-liquid interface and stimulated with IL-6/ sIL-6R and tumor necrosis factor (TNF)-a with or without the addition of sgp130, a natural inhibitor of IL-6 trans-signaling. There was a significant age-related decline in S100A8/9 and an increase in sgp130 in nasal tissue samples from patients with CRSwNP, although there was no age-related difference in IL-6/sIL-6R production.Additionally, expression of the S100A8/9 gene and protein was increased significantly by IL-6/sIL-6R plus TNF-a in normal human bronchial epithelial cells. This increase was blocked by sgp130. These results suggest that increased sgp130 in older patients may inhibit IL-6 trans-signaling, impair barrier function, and decrease S1008/9 production in elderly patients with CRSwNP. Restoration of barrier function by targeting sgp130 may be a novel treatment strategy.

Prevalence, severity, and risk factors for acute exacerbations of nasal and sinus symptoms by chronic rhinosinusitis status

“…The odds of AENSS‐Sx‐Pur declined with higher ages, excluding the current long‐term CRS status group, possibly due to differential susceptibility to viral infections which precede bacterial infections and decrease with increasing age . Yet, individuals with long‐term CRS may be at risk of developing viral respiratory infections even at older ages due to compromised epithelial barrier function, which can accompany CRS, suggestive of a disease progressive model in those with persistent CRS.…”

Age‐associated changes in chronic rhinosinusitis endotypes

“…Our previous studies reported that CRS exhibited an age‐related decline in innate barrier function in eosinophilic nasal polyps (ENP), and an age‐related decrement in neutrophilic inflammation in non‐eosinophilic nasal polyps (NENP), which reflected treatment outcomes in elderly NENP subjects . Interestingly, elderly CRS patients were characterized by increased neutrophilic proinflammatory cytokines such as IL‐1β, IL‐6, IL‐8, and TNF‐ɑ and by less responsiveness to steroid treatment in a recent study .…”

The IL6R gene polymorphisms are associated with sIL-6R, IgE and lung function in Chinese patients with asthma

“…Thus, sIL-6R plays an important role in the responses mediated by IL-6. The activity of sIL-6R is implicated in a variety of inflammatory diseases, such as inflammatory bowel disease (Brulhart et al, 2010;Rose-John et al, 2009), rheumatoid arthritis (Febbraio et al, 2010) and asthma (Robinson et al, 2015;Ullah et al, 2015;Cho et al, 2015), and there are anti-IL-6R therapies, which target sIL-6R as well as the membrane-bound mIL-6R (Mima & Nishimoto, 2009). …”