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

• Published in: PloS one Vol. 12; no. 10; p. e0186628
• Main Authors: Peuhu, Emilia, Salomaa, Siiri I, De Franceschi, Nicola, Potter, Christopher S, Sundberg, John P, Pouwels, Jeroen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.10.2017; Public Library of Science (PLoS)
• Subjects: Animals; Antibodies, Neutralizing - pharmacology; Apoptosis; Biology and Life Sciences; Biotechnology; Blocking antibodies; Care and treatment; Carrier Proteins - genetics; Carrier Proteins - immunology; Cell adhesion & migration; Cell death; Cell Proliferation; Chronic Disease; Dermatitis; Dermatitis - drug therapy; Dermatitis - genetics; Dermatitis - immunology; Dermatitis - pathology; Dermis; Diagnosis; Epidermis - drug effects; Epidermis - immunology; Epidermis - pathology; Female; Gene Deletion; Gene Expression Regulation; Genotype & phenotype; Inflammation; Inhibition; Integrin beta1 - genetics; Integrin beta1 - immunology; Integrins; Intracellular Signaling Peptides and Proteins; Keratinocytes; Keratinocytes - drug effects; Keratinocytes - immunology; Keratinocytes - pathology; Laboratories; Male; Medicine and Health Sciences; Mice; Mice, Knockout; NF-kappa B - genetics; NF-kappa B - immunology; NF-κB protein; Phenotype; Psoriasis; Receptors, Tumor Necrosis Factor, Type I - deficiency; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - immunology; Research and Analysis Methods; Rodents; Signal Transduction; Skin; Transgenic animals; Tumor necrosis factor; Tumor necrosis factor receptors; Tumor necrosis factor-TNF; Ubiquitin; Ubiquitin - genetics; Ubiquitin - immunology; United States > US; Maine; Finland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0186628

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.