Congenital deficiency reveals critical role of ISG15 in skin homeostasis.

Autor:	Malik MNH; Research Group Biomarkers for Infectious Diseases, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Waqas SF; Research Group Biomarkers for Infectious Diseases, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Zeitvogel J; Department Dermatology and Allergy, Hannover Medical School, Hannover, Germany., Cheng J; Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany., Geffers R; Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany., Gouda ZA; Department of Dermatology, Venereology and Andrology, Faculty of Medicine, and., Elsaman AM; Department of Rheumatology and Rehabilitation, Sohag University, Sohag, Egypt., Radwan AR; Department of Rheumatology and Rehabilitation, Sohag University, Sohag, Egypt., Schefzyk M; Department Dermatology and Allergy, Hannover Medical School, Hannover, Germany., Braubach P; Institute for Pathology., Auber B; Institute for Human Genetics., Olmer R; Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), and.; REBIRTH-Research Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany., Müsken M; Central Facility for Microscopy, Helmholtz Centre for Infection Research, Braunschweig, Germany., Roesner LM; Department Dermatology and Allergy, Hannover Medical School, Hannover, Germany., Gerold G; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Schuchardt S; Department of Bio- and Environmental Analytics, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany., Merkert S; Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), and.; REBIRTH-Research Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany., Martin U; Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), and.; REBIRTH-Research Center for Translational Regenerative Medicine, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany., Meissner F; Experimental Systems Immunology, Max Planck Institute of Biochemistry, Martinsried, Germany.; Institute of Innate Immunity, Department of Systems Immunology and Proteomics, Medical Faculty, University of Bonn, Bonn, Germany., Werfel T; Department Dermatology and Allergy, Hannover Medical School, Hannover, Germany., Pessler F; Research Group Biomarkers for Infectious Diseases, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.; Centre for Individualised Infection Medicine, Hannover, Germany.; Helmholtz Centre for Infection Research, Braunschweig, Germany.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2022 Feb 01; Vol. 132 (3).
DOI:	10.1172/JCI141573
Abstrakt:	Ulcerating skin lesions are manifestations of human ISG15 deficiency, a type I interferonopathy. However, chronic inflammation may not be their exclusive cause. We describe two siblings with recurrent skin ulcers that healed with scar formation upon corticosteroid treatment. Both had a homozygous nonsense mutation in the ISG15 gene, leading to unstable ISG15 protein lacking the functional domain. We characterized ISG15-/- dermal fibroblasts, HaCaT keratinocytes, and human induced pluripotent stem cell-derived vascular endothelial cells. ISG15-deficient cells exhibited the expected hyperinflammatory phenotype, but also dysregulated expression of molecules critical for connective tissue and epidermis integrity, including reduced collagens and adhesion molecules, but increased matrix metalloproteinases. ISG15-/- fibroblasts exhibited elevated ROS levels and reduced ROS scavenger expression. As opposed to hyperinflammation, defective collagen and integrin synthesis was not rescued by conjugation-deficient ISG15. Cell migration was retarded in ISG15-/- fibroblasts and HaCaT keratinocytes, but normalized under ruxolitinib treatment. Desmosome density was reduced in an ISG15-/- 3D epidermis model. Additionally, there were loose architecture and reduced collagen and desmoglein expression, which could be reversed by treatment with ruxolitinib/doxycycline/TGF-β1. These results reveal critical roles of ISG15 in maintaining cell migration and epidermis and connective tissue homeostasis, whereby the latter likely requires its conjugation to yet unidentified targets.
Databáze:	MEDLINE
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