Keratinocyte-specific deletion of SHARPIN induces atopic dermatitis-like inflammation in mice

• Published in: PloS one Vol. 15; no. 7; p. e0235295
• Main Authors: Sundberg, John P, Pratt, C Herbert, Goodwin, Leslie P, Silva, Kathleen A, Kennedy, Victoria E, Potter, Christopher S, Dunham, Anisa, Sundberg, Beth A, HogenEsch, Harm
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20-07-2020; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Arthritis; Arthritis - genetics; Arthritis - pathology; Atopic dermatitis; Biology and Life Sciences; Cell culture; Defects; Dendritic cells; Dermatitis; Dermatitis, Atopic - genetics; Dermatitis, Atopic - pathology; Disease; Disease Models, Animal; Eczema; Fibroblasts; Gene deletion; Gene Expression Regulation - genetics; Genotype & phenotype; Humans; Immunoglobulin E; Immunoglobulin E - genetics; Inflammation; Inflammation - genetics; Inflammation - pathology; Integrases - genetics; Interleukin 1; Interleukin 18; Interleukin-18 - genetics; Keratin-14 - genetics; Keratinocytes; Keratinocytes - metabolism; Keratinocytes - pathology; Laboratory animals; Lesions; Leukocytes (eosinophilic); Medicine and Health Sciences; Mice; Mutants; Mutation; Nerve Tissue Proteins - genetics; NF-kappa B - genetics; NF-κB protein; Organs; Phenotype; Phenotypes; Physiological aspects; Proteins; Recombinase; Research and Analysis Methods; Rodents; S100 Calcium-Binding Protein A4 - genetics; S100A4 protein; Signal Transduction; Skin diseases; Skin lesions; Veterinary colleges; Veterinary medicine; United States; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0235295

Spontaneous mutations in the SHANK-associated RH domain interacting protein (Sharpin) resulted in a severe autoinflammatory type of chronic proliferative dermatitis, inflammation in other organs, and lymphoid organ defects. To determine whether cell-type restricted loss of Sharpin causes similar lesions, a conditional null mutant was created. Ubiquitously expressing cre-recombinase recapitulated the phenotype seen in spontaneous mutant mice. Limiting expression to keratinocytes (using a Krt14-cre) induced a chronic eosinophilic dermatitis, but no inflammation in other organs or lymphoid organ defects. The dermatitis was associated with a markedly increased concentration of serum IgE and IL18. Crosses with S100a4-cre resulted in milder skin lesions and moderate to severe arthritis. This conditional null mutant will enable more detailed studies on the role of SHARPIN in regulating NFkB and inflammation, while the Krt14-Sharpin-/- provides a new model to study atopic dermatitis.