Inhaled ds RNA and rhinovirus evoke neutrophilic exacerbation and lung expression of thymic stromal lymphopoietin in allergic mice with established experimental asthma

Abstract

BackgroundRhinovirus infection or dsRNA stimulation increased thymic stromal lymphopoietin (TSLP), an upstream pro-allergic cytokine, in asthmatic bronchial epithelial cells. We hypothesized that dsRNA challenges superimposed on established experimental allergic asthma constitute a useful exacerbation model. We further hypothesized that TSLP is induced at dsRNA- and rhinoviral infection-induced exacerbations.MethodsAllergic mice were challenged with OVA followed by three daily intranasal challenges with dsRNA or saline. Bronchoalveolar lavage fluid (BALF) was analysed for total protein, lactate dehydrogenase (LDH), CXCL1/KC, CCL2/MCP-1 and differential cell counts. Lung tissue histology, neutrophils and TSLP, TNF-α, IFN-β and IFN-λ mRNA were examined. Alternatively, allergen-challenged mice received intranasal rhinovirus-(RV)-1B followed by lung TSLP immunostaining.ResultsIn mice with allergic airway inflammation, dsRNA challenges caused a significant exacerbation increasing lung tissue inflammation score and tissue neutrophilia. Bronchoalveolar lavage fluid neutrophils, total protein, LDH, CXCL1/KC and CCL2/MCP-1 were also increased (P < 0.01), and so were lung tissue expressions of TNF-α, IFN-λ and TSLP (P < 0.01), but IFN-β was not increased. TSLP, IFN-λ and LDH were not increased by allergen or dsRNA challenges alone, but increased exclusively at exacerbations. RV1B infection-induced exacerbation also increased lung tissue TSLP (P < 0.05).ConclusionsdsRNA-induced exacerbation in mice with experimental asthma involved general inflammation, cytokines and interferons, in agreement with previous observations in exacerbating human asthma. Additionally, both dsRNA and RV1B infection increased lung TSLP exclusively at exacerbations. Our data suggest that dsRNA challenges superimposed on allergic inflammation are suited for pharmacological studies of asthma exacerbations including the regulation of lung tissue TSLP, TNF-α, IFN-β and IFN-λ.

Double-stranded RNA evokes exacerbation in a mouse model of corticosteroid refractory asthma

“…However, our data are consistent with data published by several other authors in exacerbation models after poly(I:C) challenge [28,29,33]. These discrepancies could be due to signalling differences between live virus and poly(I:C) [34], the inflammatory background of the model or the timing of the infection or poly(I:C) challenge.…”

“…Several cytokines that have been related with neutrophilic inflammation, such as IL-1 or IL-6 are exacerbated in our model and could therefore have a role in this neutrophilia. Interestingly, KC, the mouse equivalent of IL-8, does not seem to be involved in the exacerbation associated with our model unlike in other reported models of asthma exacerbation using poly(I:C), where this particular cytokine seemed to play a key role [28,29].…”

MicroRNA-26a/-26b-COX-2-MIP-2 Loop Regulates Allergic Inflammation and Allergic Inflammation-promoted Enhanced Tumorigenic and Metastatic Potential of Cancer Cells

“…TLR3 plays a pivotal role in airway hyperresponsiveness in response to microbial infection in allergic lung inflammation (36). In mice with allergic airway inflammation, dsRNA (a ligand of TLR3) challenge causes a significant exacerbation, increasing lung tissue inflammation score and tissue neutrophilia (37). TLR3 activation induces production of allergen-specific IgE and IgG1 (38).…”

Rhinovirus infection in young children is associated with elevated airway TSLP levels

“…Of particular interest is the epithelial-derived cytokine thymic stromal lymphopoietin (TSLP), which is considered a “master Th2 cytokine” because it primes the differentiation of naïve T0 cells into Th2 lymphocytes via activation of antigen presenting cells [3]. TSLP is induced by rhinovirus infection or by exposure to double stranded (ds)RNA (viral surrogate) in the lungs of allergic mice [4], and in human bronchial epithelial cells (HBEC) [5]. Together, these data suggest that TSLP may be the missing link between innate antiviral epithelial immunity and the Th2 immune response characteristic of asthma.…”