Integrative Keratinocyte Responses to TWEAK with IL-13 and IL-22 Reveal Pathogenic Transcriptomes Associated with Atopic Dermatitis

Atopic dermatitis (AD) is characterized by dysregulated activity of keratinocytes (KCs), and IL-13 and IL-22 are considered drivers of the disease in part by stimulating these cells ( Facheris et al., 2023 Facheris P. Jeffery J. Del Duca E. Guttman-Yassky E. The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment. Cell Mol Immunol. 2023; 20: 448-474 Crossref PubMed Scopus (16) Google Scholar ; Humeau et al., 2022 Humeau M. Boniface K. Bodet C. Cytokine-mediated crosstalk between keratinocytes and T cells in atopic dermatitis. Front Immunol. 2022; 13: 801579 Crossref Scopus (18) Google Scholar ; Kim et al., 2019 Kim J. Kim B.E. Leung D.Y.M. Pathophysiology of atopic dermatitis: clinical implications. Allergy Asthma Proc. 2019; 40: 84-92 Crossref PubMed Scopus (263) Google Scholar ). Whether these cytokines act independently or with other inflammatory molecules is not clear. Previously, we reported that mice deficient in the cytokine TWEAK (TNFSF12) were resistant to developing experimental AD, with its receptor Fn14 (TNFRSF12A) prominently expressed on KCs ( Sidler et al., 2017 Sidler D. Wu P. Herro R. Claus M. Wolf D. Kawakami Y. et al. TWEAK mediates inflammation in experimental atopic dermatitis and psoriasis. Nat Commun. 2017; 8: 15395 Crossref PubMed Scopus (47) Google Scholar ). We also showed that deletion of Fn14 only in KCs protected mice from developing maximal AD phenotypes, and therapeutic blocking of TWEAK was as effective as blocking IL-13 in reducing AD symptoms ( Gupta et al., 2023 Gupta R.K. Miller J. Croft M. TNF-like weak inducer of apoptosis inhibition is comparable to IL-13 blockade in ameliorating atopic dermatitis inflammation. Allergy. 2023; 79: 116-127 Crossref Scopus (0) Google Scholar ). Gene set enrichment analysis from lesional skin samples has further suggested that there is a strong association of AD with TWEAK and Fn14 activity ( Sidler et al., 2017 Sidler D. Wu P. Herro R. Claus M. Wolf D. Kawakami Y. et al. TWEAK mediates inflammation in experimental atopic dermatitis and psoriasis. Nat Commun. 2017; 8: 15395 Crossref PubMed Scopus (47) Google Scholar ), and TWEAK and/or its receptor were found upregulated in AD skin lesions ( Chen et al., 2011 Chen Y. Lind Enoksson S. Johansson C. Karlsson M.A. Lundeberg L. Nilsson G. et al. The expression of BAFF, APRIL and TWEAK is altered in eczema skin but not in the circulation of atopic and seborrheic eczema patients. PLoS One. 2011; 6: e22202 Crossref PubMed Scopus (26) Google Scholar ; Liu et al., 2020 Liu Q. Wang H. Wang X. Lu M. Tan X. Peng L. et al. Experimental atopic dermatitis is dependent on the TWEAK/Fn14 signaling pathway. Clin Exp Immunol. 2020; 199: 56-67 Crossref PubMed Scopus (8) Google Scholar ; Zimmermann et al., 2011 Zimmermann M. Koreck A. Meyer N. Basinski T. Meiler F. Simone B. et al. TNF-like weak inducer of apoptosis (TWEAK) and TNF-α cooperate in the induction of keratinocyte apoptosis. J Allergy Clin Immunol. 2011; 127 (207.e1-10): 200-207 Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar ).