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Interferon-? deficiency at asthma exacerbation promotes MLKL mediated necroptosis.


ABSTRACT: Defective production of antiviral interferon (IFN)-? 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-? could contribute to necrotic cell death in a model of asthma exacerbations. Wild-type and IFN-?-/- 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-? 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-? augments markers of necroptotic cell death at exacerbation. Our data thus suggest a novel role of deficient IFN-? production at viral-induced exacerbation.

SUBMITTER: Cerps SC 

PROVIDER: S-EPMC5844912 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Interferon-β deficiency at asthma exacerbation promotes MLKL mediated necroptosis.

Cerps Samuel C SC   Menzel Mandy M   Mahmutovic Persson Irma I   Bjermer Leif L   Akbarshahi Hamid H   Uller Lena L  

Scientific reports 20180309 1


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<sup>-/-</sup> mice were given saline or house dust mite (HDM) intranasally for 3 weeks to induce inflamm  ...[more]

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