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

Abstract

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 <i>IL17A</i> ⁺ T-cells and 95% of <i>IL17F</i> ⁺ T-cells in psoriasis skin. The expression of <i>IL23A</i> in DC subsets was also downregulated by IL-17A blockade. The expression of IL-17-driven inflammatory mediators (<i>IL36G</i>, <i>S100A8</i>, <i>DEFB4A</i>, and <i>DEFB4B</i>) 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 <i>BDCA-3</i> (<i>THBD</i>) and <i>DCIR</i> (<i>CLEC4A</i>) was increased in posttreatment psoriasis lesional skin compared to pretreatment psoriasis lesional skin. In addition, IL-17A blockade induced higher expression of <i>CD1C</i> and <i>CD14</i>, which are markers of CD1c⁺ CD14⁺ 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.