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Congenital deficiency reveals critical role of ISG15 in skin homeostasis

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 no...

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Autores principales: Malik, Muhammad Nasir Hayat, Waqas, Syed Fakhar-ul-Hassnain, Zeitvogel, Jana, Cheng, Jingyuan, Geffers, Robert, Gouda, Zeinab Abu-Elbaha, Elsaman, Ahmed Mahrous, Radwan, Ahmed R., Schefzyk, Matthias, Braubach, Peter, Auber, Bernd, Olmer, Ruth, Müsken, Mathias, Roesner, Lennart M., Gerold, Gisa, Schuchardt, Sven, Merkert, Sylvia, Martin, Ulrich, Meissner, Felix, Werfel, Thomas, Pessler, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8803340/
https://www.ncbi.nlm.nih.gov/pubmed/34847081
http://dx.doi.org/10.1172/JCI141573
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author Malik, Muhammad Nasir Hayat
Waqas, Syed Fakhar-ul-Hassnain
Zeitvogel, Jana
Cheng, Jingyuan
Geffers, Robert
Gouda, Zeinab Abu-Elbaha
Elsaman, Ahmed Mahrous
Radwan, Ahmed R.
Schefzyk, Matthias
Braubach, Peter
Auber, Bernd
Olmer, Ruth
Müsken, Mathias
Roesner, Lennart M.
Gerold, Gisa
Schuchardt, Sven
Merkert, Sylvia
Martin, Ulrich
Meissner, Felix
Werfel, Thomas
Pessler, Frank
author_facet Malik, Muhammad Nasir Hayat
Waqas, Syed Fakhar-ul-Hassnain
Zeitvogel, Jana
Cheng, Jingyuan
Geffers, Robert
Gouda, Zeinab Abu-Elbaha
Elsaman, Ahmed Mahrous
Radwan, Ahmed R.
Schefzyk, Matthias
Braubach, Peter
Auber, Bernd
Olmer, Ruth
Müsken, Mathias
Roesner, Lennart M.
Gerold, Gisa
Schuchardt, Sven
Merkert, Sylvia
Martin, Ulrich
Meissner, Felix
Werfel, Thomas
Pessler, Frank
author_sort Malik, Muhammad Nasir Hayat
collection PubMed
description 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.
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spelling pubmed-88033402022-02-04 Congenital deficiency reveals critical role of ISG15 in skin homeostasis Malik, Muhammad Nasir Hayat Waqas, Syed Fakhar-ul-Hassnain Zeitvogel, Jana Cheng, Jingyuan Geffers, Robert Gouda, Zeinab Abu-Elbaha Elsaman, Ahmed Mahrous Radwan, Ahmed R. Schefzyk, Matthias Braubach, Peter Auber, Bernd Olmer, Ruth Müsken, Mathias Roesner, Lennart M. Gerold, Gisa Schuchardt, Sven Merkert, Sylvia Martin, Ulrich Meissner, Felix Werfel, Thomas Pessler, Frank J Clin Invest Research Article 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. American Society for Clinical Investigation 2022-02-01 2022-02-01 /pmc/articles/PMC8803340/ /pubmed/34847081 http://dx.doi.org/10.1172/JCI141573 Text en © 2022 Malik et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Malik, Muhammad Nasir Hayat
Waqas, Syed Fakhar-ul-Hassnain
Zeitvogel, Jana
Cheng, Jingyuan
Geffers, Robert
Gouda, Zeinab Abu-Elbaha
Elsaman, Ahmed Mahrous
Radwan, Ahmed R.
Schefzyk, Matthias
Braubach, Peter
Auber, Bernd
Olmer, Ruth
Müsken, Mathias
Roesner, Lennart M.
Gerold, Gisa
Schuchardt, Sven
Merkert, Sylvia
Martin, Ulrich
Meissner, Felix
Werfel, Thomas
Pessler, Frank
Congenital deficiency reveals critical role of ISG15 in skin homeostasis
title Congenital deficiency reveals critical role of ISG15 in skin homeostasis
title_full Congenital deficiency reveals critical role of ISG15 in skin homeostasis
title_fullStr Congenital deficiency reveals critical role of ISG15 in skin homeostasis
title_full_unstemmed Congenital deficiency reveals critical role of ISG15 in skin homeostasis
title_short Congenital deficiency reveals critical role of ISG15 in skin homeostasis
title_sort congenital deficiency reveals critical role of isg15 in skin homeostasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8803340/
https://www.ncbi.nlm.nih.gov/pubmed/34847081
http://dx.doi.org/10.1172/JCI141573
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