1. Congenital deficiency reveals critical role of ISG15 in skin homeostasis
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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, Musken, Mathias, Roesner, Lennart M., Gerold, Gisa, Schuchardt, Sven, Merkert, Sylvia, Martin, Ulrich, Meissner, Felix, Werfel, Thomas, and Pessler, Frank
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Interferon -- Health aspects -- Genetic aspects -- Case studies ,Genetic disorders -- Complications and side effects -- Case studies -- Diagnosis ,Immunity -- Genetic aspects -- Health aspects -- Case studies ,Skin -- Ulcers ,Pediatric research ,Health care industry - Abstract
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.sup.-/-] 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.sup.-/-] 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.sup.-/-] fibroblasts and HaCaT keratinocytes, but normalized under ruxolitinib treatment. Desmosome density was reduced in an [ISG15.sup.-/-] 3D epidermis model. Additionally, there were loose architecture and reduced collagen and desmoglein expression, which could be reversed by treatment with ruxolitinib/doxycycline/TGF-[beta]1. 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., Introduction Monogenic type I interferonopathies are a heterogeneous group of autoinflammatory and autoimmune disorders characterized by persistently elevated levels of type I interferons (IFN-I) (1-3). The underlying molecular mechanisms are [...]
- Published
- 2022
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