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

Document Type

Article

Publication Date

10-17-2017

Keywords

Animals, Antibodies, Neutralizing, Antigens, CD29, Apoptosis, Carrier Proteins, Cell Proliferation, Chronic Disease, Dermatitis, Epidermis, Female, Gene Deletion, Gene Expression Regulation, Inflammation, Keratinocytes, Male, Mice, Mice, Knockout, NF-kappa B, Phenotype, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, Ubiquitin

JAX Source

PLoS One 2017 Oct 17; 12(10):e0186628.

Volume

12

Issue

10

First Page

0186628

Last Page

0186628

ISSN

1932-6203

PMID

29040328

DOI

https://doi.org/10.1371/journal.pone.0186628

Grant

T32 DK07449-28, AR04928

Abstract

SHARPIN (Shank-Associated RH Domain-Interacting Protein) is a component of the linear ubiquitin chain assembly complex (LUBAC), which enhances TNF-induced NF-κB activity. SHARPIN-deficient (Sharpincpdm/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 Sharpincpdm/cpdm mice is due to increased integrin activity or is secondary to inflammation. In addition, the functional contribution of increased integrin activation to the Sharpincpdm/cpdm phenotype has not been investigated. Here, we find increased integrin activity in keratinocytes from Tnfr1-/- Sharpincpdm/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 Sharpincpdm/cpdm skin phenotype. Treatment with an integrin beta 1 function blocking antibody reduced epidermal hyperproliferation and epidermal thickness in Sharpincpdm/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 Sharpincpdm/cpdm mice. PLoS One 2017 Oct 17; 12(10):e0186628.

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