| 1. |
- Cerps, Samuel C., et al.
(author)
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Interferon-β deficiency at asthma exacerbation promotes MLKL mediated necroptosis
- 2018
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Journal article (peer-reviewed)abstract
- Defective production of antiviral interferon (IFN)-β is thought to contribute to rhinovirus-induced asthma exacerbations. These exacerbations are associated with elevated lung levels of lactate dehydrogenase (LDH), indicating occurrence of cell necrosis. We thus hypothesized that reduced lung IFN-β could contribute to necrotic cell death in a model of asthma exacerbations. Wild-type and IFN-β-/- mice were given saline or house dust mite (HDM) intranasally for 3 weeks to induce inflammation. Double-stranded RNA (dsRNA) was then given for additional 3 days to induce exacerbation. HDM induced an eosinophilic inflammation, which was not associated with increased expression of cleaved caspase-3, cleaved PARP or elevated bronchoalveolar lavage fluid (BALF) LDH levels in wild-type. However, exacerbation evoked by HDM + dsRNA challenges increased BALF levels of LDH, apoptotic markers and the necroptotic markers receptor-interacting protein (RIP)-3 and phosphorylation of mixed linage kinase domain-like protein (pMLKL), compared to HDM + saline. Absence of IFN-β at exacerbation further increased BALF LDH and protein expression of pMLKL compared to wild-type. We demonstrate that cell death markers are increased at viral stimulus-induced exacerbation in mouse lungs, and that absence of IFN-β augments markers of necroptotic cell death at exacerbation. Our data thus suggest a novel role of deficient IFN-β production at viral-induced exacerbation.
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| 2. |
- Mahmutovic Persson, Irma, et al.
(author)
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IL-1β mediates lung neutrophilia and IL-33 expression in a mouse model of viral-induced asthma exacerbation
- 2018
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In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 19:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Viral-induced asthma exacerbations, which exhibit both Th1-type neutrophilia and Th2-type inflammation, associate with secretion of Interleukin (IL)-1β. IL-1β induces neutrophilic inflammation. It may also increase Th2-type cytokine expression. We hypothesised that IL-1β is causally involved in both Th1 and Th2 features of asthma exacerbations. This hypothesis is tested in our mouse model of viral stimulus-induced asthma exacerbation.METHOD: Wild-type (WT) and IL-1β deficient (IL-1β-/-) mice received house dust mite (HDM) or saline intranasally during three weeks followed by intranasal dsRNA (PolyI:C molecule known for its rhinovirus infection mimic) for three consecutive days to provoke exacerbation. Bronchoalveolar lavage fluid was analysed for inflammatory cells and total protein. Lung tissues were stained for neutrophilic inflammation and IL-33. Tissue homogenates were analysed for mRNA expression of Muc5ac, CXCL1/KC, TNF-α, CCL5, IL-25, TSLP, IL-33, IL-1β, CCL11 and CCL2 using RT-qPCR.RESULTS: Expression of IL-1β, neutrophil chemoattractants, CXCL1 and CCL5, the Th2-upstream cytokine IL-33, and Muc5ac were induced at exacerbation in WT mice and were significantly inhibited in IL-1β-/- mice at exacerbation. Effects of HDM alone were not reduced in IL-1β-deficient mice.CONCLUSION: Without being involved in the baseline HDM-induced allergic asthma, IL-1β signalling was required to induce neutrophil chemotactic factors, IL-33, and Muc5ac expression at viral stimulus-induced exacerbation. We suggest that IL-1β has a role both in neutrophilic and Th2 inflammation at viral-induced asthma exacerbations.
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