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Interferon-β deficiency at asthma exacerbation promotes MLKL mediated necroptosis

Cerps, Samuel C. LU ; Menzel, Mandy LU ; Mahmutovic Persson, Irma LU ; Bjermer, Leif LU ; Akbarshahi, Hamid LU and Uller, Lena LU (2018) In Scientific Reports 8(1).
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... (More)

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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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
8
issue
1
article number
4248
publisher
Nature Publishing Group
external identifiers
  • pmid:29523863
  • scopus:85043976967
ISSN
2045-2322
DOI
10.1038/s41598-018-22557-6
language
English
LU publication?
yes
id
948e9011-fc09-455e-b90b-ef83e3bec8ac
date added to LUP
2018-03-28 15:17:48
date last changed
2024-03-18 07:25:13
@article{948e9011-fc09-455e-b90b-ef83e3bec8ac,
  abstract     = {{<p>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 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.</p>}},
  author       = {{Cerps, Samuel C. and Menzel, Mandy and Mahmutovic Persson, Irma and Bjermer, Leif and Akbarshahi, Hamid and Uller, Lena}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Interferon-β deficiency at asthma exacerbation promotes MLKL mediated necroptosis}},
  url          = {{http://dx.doi.org/10.1038/s41598-018-22557-6}},
  doi          = {{10.1038/s41598-018-22557-6}},
  volume       = {{8}},
  year         = {{2018}},
}