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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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-02-01
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| Series: | The Journal of Clinical Investigation |
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| Online Access: | https://doi.org/10.1172/JCI141573 |
| _version_ | 1828197575199555584 |
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| author | Muhammad Nasir Hayat Malik Syed Fakhar-ul-Hassnain Waqas Jana Zeitvogel Jingyuan Cheng Robert Geffers Zeinab Abu-Elbaha Gouda Ahmed Mahrous Elsaman Ahmed R. Radwan Matthias Schefzyk Peter Braubach Bernd Auber Ruth Olmer Mathias Müsken Lennart M. Roesner Gisa Gerold Sven Schuchardt Sylvia Merkert Ulrich Martin Felix Meissner Thomas Werfel Frank Pessler |
| author_facet | Muhammad Nasir Hayat Malik Syed Fakhar-ul-Hassnain Waqas Jana Zeitvogel Jingyuan Cheng Robert Geffers Zeinab Abu-Elbaha Gouda Ahmed Mahrous Elsaman Ahmed R. Radwan Matthias Schefzyk Peter Braubach Bernd Auber Ruth Olmer Mathias Müsken Lennart M. Roesner Gisa Gerold Sven Schuchardt Sylvia Merkert Ulrich Martin Felix Meissner Thomas Werfel Frank Pessler |
| author_sort | Muhammad Nasir Hayat Malik |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T10:21:39Z |
| format | Article |
| id | doaj.art-954f97e3aee74d59a2deee752c511caf |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-04-12T10:21:39Z |
| publishDate | 2022-02-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-954f97e3aee74d59a2deee752c511caf2022-12-22T03:37:05ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-02-011323Congenital deficiency reveals critical role of ISG15 in skin homeostasisMuhammad Nasir Hayat MalikSyed Fakhar-ul-Hassnain WaqasJana ZeitvogelJingyuan ChengRobert GeffersZeinab Abu-Elbaha GoudaAhmed Mahrous ElsamanAhmed R. RadwanMatthias SchefzykPeter BraubachBernd AuberRuth OlmerMathias MüskenLennart M. RoesnerGisa GeroldSven SchuchardtSylvia MerkertUlrich MartinFelix MeissnerThomas WerfelFrank PesslerUlcerating 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.https://doi.org/10.1172/JCI141573Autoimmunity |
| spellingShingle | Muhammad Nasir Hayat Malik Syed Fakhar-ul-Hassnain Waqas Jana Zeitvogel Jingyuan Cheng Robert Geffers Zeinab Abu-Elbaha Gouda Ahmed Mahrous Elsaman Ahmed R. Radwan Matthias Schefzyk Peter Braubach Bernd Auber Ruth Olmer Mathias Müsken Lennart M. Roesner Gisa Gerold Sven Schuchardt Sylvia Merkert Ulrich Martin Felix Meissner Thomas Werfel Frank Pessler Congenital deficiency reveals critical role of ISG15 in skin homeostasis The Journal of Clinical Investigation Autoimmunity |
| 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 | Autoimmunity |
| url | https://doi.org/10.1172/JCI141573 |
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