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Wasserer, S.* ; Seiringer, P.* ; Kurzen, N.* ; Jargosch, M. ; Eigemann, J. ; Aydin, G.* ; Raunegger, T.* ; Schmidt-Weber, C.B. ; Eyerich, S. ; Biedermann, T.* ; Eyerich, K.* ; Lauffer, F.*

TYK2 inhibition improves clinical and molecular hallmarks in various subtypes of cutaneous lupus.

Br. J. Dermatol. 193, 1192-1203 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
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BACKGROUND: Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease (ISD) with various clinical subtypes. Though the pathogenesis is not yet fully understood T cell mediated autoimmunity and elevated levels of type 1 interferons are two major factors contributing to the development of cutaneous lesions. Type 1 interferons transduce their signal via TYK2. OBJECTIVE: To investigate the impact of TYK2 signaling in pre-clinical models of CLE. METHODS: CLE skin biopsies were investigated by RNA-seq and immunohistochemistry. T cells isolated from CLE skin biopsies (lesional T cells) were re-stimulated with anti-CD2/anti-CD28 and cytokine release was quantified by ELISA and Luminex. Primary human keratinocytes and three-dimensional skin models were stimulated with IFN-α or lesional T-cell supernatant in presence or absence of the TYK2 inhibitor deucravacitinib followed by RNA-seq. Skin biopsies from different CLE subtypes were treated ex vivo with deucravacitinib followed by qRT-PCR. RESULTS: Bulk RNA sequencing revealed a strong correlation between TYK2 and interface dermatitis (ID), a histological hallmark of CLE. Immunohistochemistry confirmed a high abundance of TYK2 amongst different CLE subtypes. Inhibiting TYK2 reduced inflammation and normalized epidermal impairments in primary human keratinocytes, reconstructed human epidermis and CLE T cells. Ex vivo TYK2 inhibition in CLE skin biopsies reduced IFN-response- and necroptosis-related gene expression. Finally, four patients with different therapy-refractory CLE (acute, subacute, chronic discoid, chilblain CLE) were successfully treated with deucravacitinib. CONCLUSION: IFN-α and T cell derived cytokines both contribute to skin inflammation in CLE. TYK2 inhibition is a promising approach for different subtypes of CLE as it controls inflammation in various pre-clinical models and therapy refractory CLE patients.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Interferon-alpha; Immune-response; Erythematosus; Expression; Anifrolumab; Il-22
ISSN (print) / ISBN 0007-0963
e-ISSN 1365-2133
Journal British Journal of Dermatology - BJD
Quellenangaben Volume: 193, Issue: 6, Pages: 1192-1203 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Reviewing status Peer reviewed
Institute(s) Institute for Allergy Research (IAF)
Grants German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)
Bristol Myers Squibb