AUTHOR=Kim Jaehwan , Lee Jongmi , Li Xuan , Kunjravia Norma , Rambhia Darshna , Cueto Inna , Kim Katherine , Chaparala Vasuma , Ko Younhee , Garcet Sandra , Zhou Wei , Cao Junyue , Krueger James G. 

TITLE=Multi-omics segregate different transcriptomic impacts of anti-IL-17A blockade on type 17 T-cells and regulatory immune cells in psoriasis skin

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1250504

DOI=10.3389/fimmu.2023.1250504

ISSN=1664-3224

ABSTRACT=<p>Durable psoriasis improvement has been reported in a subset of psoriasis patients after treatment withdrawal of biologics blocking IL-23/Type 17 T-cell (T17) autoimmune axis. However, it is not well understood if systemic blockade of the IL-23/T17 axis promotes immune tolerance in psoriasis skin. The purpose of the study was to find translational evidence that systemic IL-17A blockade promotes regulatory transcriptome modification in human psoriasis skin immune cell subsets. We analyzed human psoriasis lesional skin 6 mm punch biopsy tissues before and after systemic IL-17A blockade using the muti-genomics approach integrating immune cell-enriched scRNA-seq (n = 18), microarray (n = 61), and immunohistochemistry (n = 61) with repository normal control skin immune cell-enriched scRNA-seq (n = 10) and microarray (n = 8) data. For the T17 axis transcriptome, systemic IL-17A blockade depleted 100% of <italic>IL17A</italic><sup>+</sup> T-cells and 95% of <italic>IL17F</italic><sup>+</sup> T-cells in psoriasis skin. The expression of <italic>IL23A</italic> in DC subsets was also downregulated by IL-17A blockade. The expression of IL-17-driven inflammatory mediators (<italic>IL36G</italic>, <italic>S100A8</italic>, <italic>DEFB4A</italic>, and <italic>DEFB4B</italic>) in suprabasal keratinocytes was correlated with psoriasis severity and was downregulated by IL-17A blockade. For the regulatory DC transcriptome, the proportion of regulatory semimature DCs expressing regulatory DC markers of <italic>BDCA-3</italic> (<italic>THBD</italic>) and <italic>DCIR</italic> (<italic>CLEC4A</italic>) was increased in posttreatment psoriasis lesional skin compared to pretreatment psoriasis lesional skin. In addition, IL-17A blockade induced higher expression of <italic>CD1C</italic> and <italic>CD14</italic>, which are markers of CD1c<sup>+</sup> CD14<sup>+</sup> dendritic cell (DC) subset that suppresses antigen-specific T-cell responses, in posttreatment regulatory semimature DCs compared to pretreatment regulatory semimature DCs. In conclusion, systemic IL-17A inhibition not only blocks the entire IL-23/T17 cell axis but also promotes regulatory gene expression in regulatory DCs in human psoriasis skin.</p>