A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Integrin beta 1 inhibition alleviates the chronic hyperproliferative dermatitis phenotype of SHARPIN-deficient mice
Tekijät: Peuhu E, Salomaa SI, De Franceschi N, Potter CS, Sundberg JP, Pouwels J
Kustantaja: PUBLIC LIBRARY SCIENCE
Julkaisuvuosi: 2017
Journal: PLoS ONE
Tietokannassa oleva lehden nimi: PLOS ONE
Lehden akronyymi: PLOS ONE
Artikkelin numero: ARTN e0186628
Vuosikerta: 12
Numero: 10
Sivujen määrä: 14
ISSN: 1932-6203
DOI: https://doi.org/10.1371/journal.pone.0186628
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/27475074
SHARPIN (Shank-Associated RH Domain-Interacting Protein) is a component of the linear ubiquitin chain assembly complex (LUBAC), which enhances TNF-induced NF-kappa B activity. SHARPIN-deficient (Sharpin(cpdm/cpdm)) mice display multi-organ inflammation and chronic proliferative dermatitis (cpdm) due to TNF-induced keratinocyte apoptosis. In cells, SHARPIN also inhibits integrins independently of LUBAC, but it has remained enigmatic whether elevated integrin activity levels in the dermis of Sharpin(cpdm/cpdm) mice is due to increased integrin activity or is secondary to inflammation. In addition, the functional contribution of increased integrin activation to the Sharpin(cpdm/cpdm) phenotype has not been investigated. Here, we find increased integrin activity in keratinocytes from Tnfr1(-/-) Sharpin(cpdm/cpdm) double knockout mice, which do not display chronic inflammation or proliferative dermatitis, thus suggesting that SHARPIN indeed acts as an integrin inhibitor in vivo. In addition, we present evidence for a functional contribution of integrin activity to the Sharpin(cpdm/cpdm) skin phenotype. Treatment with an integrin beta 1 function blocking antibody reduced epidermal hyperproliferation and epidermal thickness in Sharpin(cpdm/cpdm) mice. Our data indicate that, while TNF-induced cell death triggers the chronic inflammation and proliferative dermatitis, absence of SHARPIN-dependent integrin inhibition exacerbates the epidermal hyperproliferation in Sharpin(cpdm/cpdm) mice.
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