Multi-omics segregate different transcriptomic impacts of anti-IL-17A blockade on type 17 T-cells and regulatory immune cells in psoriasis skin.
Autor: | Kim J; Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, United States.; Dermatology Section, Veterans Affairs Northern California Health Care System, Mather, CA, United States.; Department of Dermatology, University of California, Davis, Sacramento, CA, United States., Lee J; Dermatology Section, Veterans Affairs Northern California Health Care System, Mather, CA, United States., Li X; Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, United States., Kunjravia N; Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, United States., Rambhia D; Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, United States., Cueto I; Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, United States., Kim K; Dermatology Section, Veterans Affairs Northern California Health Care System, Mather, CA, United States.; Department of Dermatology, University of California, Davis, Sacramento, CA, United States., Chaparala V; Dermatology Section, Veterans Affairs Northern California Health Care System, Mather, CA, United States., Ko Y; Department of Dermatology, University of California, Davis, Sacramento, CA, United States.; Division of Biomedical Engineering, Hankuk University of Foreign Studies, Seoul, Republic of Korea., Garcet S; Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, United States.; Research Bioinformatics, Center for Clinical and Translational Science, The Rockefeller University, New York, NY, United States., Zhou W; Laboratory of Single-cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, United States., Cao J; Laboratory of Single-cell Genomics and Population Dynamics, The Rockefeller University, New York, NY, United States., Krueger JG; Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, United States. |
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Jazyk: | angličtina |
Zdroj: | Frontiers in immunology [Front Immunol] 2023 Sep 12; Vol. 14, pp. 1250504. Date of Electronic Publication: 2023 Sep 12 (Print Publication: 2023). |
DOI: | 10.3389/fimmu.2023.1250504 |
Abstrakt: | 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 IL17A + T-cells and 95% of IL17F + T-cells in psoriasis skin. The expression of IL23A in DC subsets was also downregulated by IL-17A blockade. The expression of IL-17-driven inflammatory mediators ( IL36G , S100A8 , DEFB4A , and DEFB4B ) 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 BDCA-3 ( THBD ) and DCIR ( CLEC4A ) was increased in posttreatment psoriasis lesional skin compared to pretreatment psoriasis lesional skin. In addition, IL-17A blockade induced higher expression of CD1C and CD14 , 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. Competing Interests: JK has received research funds from AbbVie and Novartis. JGK. has received research support from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Kim, Lee, Li, Kunjravia, Rambhia, Cueto, Kim, Chaparala, Ko, Garcet, Zhou, Cao and Krueger.) |
Databáze: | MEDLINE |
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