Abstract
BackgroundSubstance P (SP) and toll‐like receptors (TLRs) contribute to airway disease, particularly during viral infection. We recently demonstrated that SP can act as an initial response to viral stimuli in the upper airway by upregulating TLRs in the nasal epithelia (the SP‐TLR axis). Patients with allergic rhinitis (AR) suffer from prolonged airway infections. The aim of the present study was to examine if patients with AR exhibit a disturbance in the SP‐TLR axis.MethodHuman nasal biopsies and human nasal epithelial cells (HNEC) from healthy volunteers and patients with AR were cultured in the presence of SP. Epithelial expression of TLR4, neutral endopeptidase (NEP) and neurokinin 1 (NK1) were evaluated with flow cytometry and/or quantitative polymerase chain reaction after 30 min to 24 h. The effect of SP on nasal lipopolysaccharide‐induced interleukin‐8 (IL‐8) release was investigated.ResultsSP stimulation of tissue from healthy volunteers resulted in a transient increase of the TLR4 expression, whereas stimulation of AR patient‐derived material led to a delayed and prolonged upregulation of TLR4. NEP expression in HNEC was lower in AR than healthy controls whereas NK1 receptor expression was increased. SP pretreatment increased TLR4‐dependent IL‐8 expression in healthy controls, but not in AR.ConclusionsSP‐induced regulation of TLR4 in the human nasal mucosa is disturbed in AR. An altered SP‐mediated innate immune response may contribute to the dysfunctional and often prolonged responses to infection in AR.
Highlights
Substance P (SP) and toll‐like receptors (TLRs) contribute to airway disease, during viral infection
The present study demonstrates that the ability for SP to regulate innate immunity is impaired in patients with allergic rhinitis (AR), with a heightened and prolonged upregulation of TLR4, and an associated lack of
Expected increased response in LPS. These changes may be attributed to differences in the expression of neutral endopeptidase (NEP) and NK‐1 receptors (NK1R), which are known to regulate expression and activity of SP
Summary
Allergic rhinitis (AR) is characterised by seasonal or persistent inflammation in the upper airways, leading to rhinorrhoea, nasal congestion, itching, and sneezing. It is a well‐founded clinical observation that patients with AR often are more prone to develop infectious airway disease than nonallergic individuals. SP, released following stimulation with the viral mimetic and TLR7 agonist R837 induced a rapid increase in the expression of several epithelial TLRs including TLR3 and TLR4.13 it is tempting to conclude that this SP‐TLR axis primes the nasal mucosa for incoming infections. As AR is associated with alterations in the expression of SP, the present study was designed to compare elements in SP‐TLR axis in nasal biopsies and epithelial cells derived from patients with AR with corresponding material from healthy individuals. Cells from passages 2–5 were used, and all were positive for EpCAM (>90%), an epithelial‐specific adhesion molecule
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