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J Clin Invest ; 132(3)2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34847081


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-ß1. 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.

Citocinas/deficiência , Derme/metabolismo , Fibroblastos/metabolismo , Homeostase , Queratinócitos/metabolismo , Ubiquitinas/deficiência , Linhagem Celular Transformada , Citocinas/metabolismo , Humanos , Ubiquitinas/metabolismo
JAAD Case Rep ; 12: 67-69, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34041335
Exp Dermatol ; 18(7): 653-5, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19196345


BACKGROUND/PURPOSE: Using a new eosinophil isolation kit, we were not able to confirm our previous findings of a delayed apoptosis of eosinophils in atopic dermatitis. Thus, we investigated whether this new isolation kit modulates the functional activity of eosinophils. METHODS: Peripheral blood eosinophils were isolated with the new isolation kit as well as conventionally with anti-CD16-conjugated MicroBeads. We analysed viability, apoptosis, CD69 and CD95 expression, streptavidin binding and superoxide anion release. RESULTS: Purity of eosinophils was higher using the new isolation kit (P < 0.05). However, these eosinophils had a decreased survival (P < 0.05-0.01), presented morphological features of apoptosis, showed an increased percentage of apoptotic nuclei (P < 0.01), an increased release of superoxide anions (P < 0.05), a higher expression of CD69 and CD95 (P < 0.05) and an increased binding to streptavidin compared to eosinophils isolated with anti-CD16 conjugated MicroBeads. CONCLUSION: The new eosinophil isolation kit should not be used for the investigation of eosinophils as it potently affects their functional activity.

Separação Celular/métodos , Eosinófilos/citologia , Microesferas , Receptores de IgG , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose , Sobrevivência Celular , Células Cultivadas , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Eosinófilos/imunologia , Humanos , Lectinas Tipo C , Superóxidos/metabolismo , Receptor fas/metabolismo