Integrin beta 1 inhibition alleviates the chronic hyperproliferative dermatitis phenotype of SHARPIN-deficient mice

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http://hdl.handle.net/10138/231446

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Peuhu , E , Salomaa , S I , De Franceschi , N , Potter , C S , Sundberg , J P & Pouwels , J 2017 , ' Integrin beta 1 inhibition alleviates the chronic hyperproliferative dermatitis phenotype of SHARPIN-deficient mice ' , PLoS One , vol. 12 , no. 10 , 0186628 . https://doi.org/10.1371/journal.pone.0186628

Title: Integrin beta 1 inhibition alleviates the chronic hyperproliferative dermatitis phenotype of SHARPIN-deficient mice
Author: Peuhu, Emilia; Salomaa, Siiri I.; De Franceschi, Nicola; Potter, Christopher S.; Sundberg, John P.; Pouwels, Jeroen
Contributor: University of Helsinki, Research Programs Unit
Date: 2017-10-17
Language: eng
Number of pages: 14
Belongs to series: PLoS One
ISSN: 1932-6203
URI: http://hdl.handle.net/10138/231446
Abstract: 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.
Subject: NF-KAPPA-B
CHRONIC PROLIFERATIVE DERMATITIS
CHAIN ASSEMBLY COMPLEX
TERMINAL DIFFERENTIATION
EPIDERMAL PROLIFERATION
T-CELLS
SKIN
IMMUNE
DISEASE
BETA-1-INTEGRIN
3111 Biomedicine
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