Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade
Abstract Biologic therapies targeting the IL-23/IL-17 axis have transformed the treatment of psoriasis. However, the early mechanisms of action of these drugs remain poorly understood. Here, we perform longitudinal single-cell RNA-sequencing in affected individuals receiving IL-23 inhibitor therapy....
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-44994-w |
| _version_ | 1827326929491984384 |
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| author | Luc Francis Daniel McCluskey Clarisse Ganier Treasa Jiang Xinyi Du-Harpur Jeyrroy Gabriel Pawan Dhami Yogesh Kamra Sudha Visvanathan Jonathan N. Barker Catherine H. Smith Francesca Capon Satveer K. Mahil |
| author_facet | Luc Francis Daniel McCluskey Clarisse Ganier Treasa Jiang Xinyi Du-Harpur Jeyrroy Gabriel Pawan Dhami Yogesh Kamra Sudha Visvanathan Jonathan N. Barker Catherine H. Smith Francesca Capon Satveer K. Mahil |
| author_sort | Luc Francis |
| collection | DOAJ |
| description | Abstract Biologic therapies targeting the IL-23/IL-17 axis have transformed the treatment of psoriasis. However, the early mechanisms of action of these drugs remain poorly understood. Here, we perform longitudinal single-cell RNA-sequencing in affected individuals receiving IL-23 inhibitor therapy. By profiling skin at baseline, day 3 and day 14 of treatment, we demonstrate that IL-23 blockade causes marked gene expression shifts, with fibroblast and myeloid populations displaying the most extensive changes at day 3. We also identify a transient WNT5A+/IL24+ fibroblast state, which is only detectable in lesional skin. In-silico and in-vitro studies indicate that signals stemming from these WNT5A+/IL24+ fibroblasts upregulate multiple inflammatory genes in keratinocytes. Importantly, the abundance of WNT5A+/IL24+ fibroblasts is significantly reduced after treatment. This observation is validated in-silico, by deconvolution of multiple transcriptomic datasets, and experimentally, by RNA in-situ hybridization. These findings demonstrate that the evolution of inflammatory fibroblast states is a key feature of resolving psoriasis skin. |
| first_indexed | 2024-03-07T14:52:37Z |
| format | Article |
| id | doaj.art-7ba2923c9a9945248d418768b1ba2572 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:37Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-7ba2923c9a9945248d418768b1ba25722024-03-05T19:37:08ZengNature PortfolioNature Communications2041-17232024-01-0115111410.1038/s41467-024-44994-wSingle-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockadeLuc Francis0Daniel McCluskey1Clarisse Ganier2Treasa Jiang3Xinyi Du-Harpur4Jeyrroy Gabriel5Pawan Dhami6Yogesh Kamra7Sudha Visvanathan8Jonathan N. Barker9Catherine H. Smith10Francesca Capon11Satveer K. Mahil12St John’s Institute of Dermatology, King’s College London and Guy’s and St Thomas’ NHS Foundation TrustDepartment of Medical and Molecular Genetics, King’s College LondonCenter of Gene Therapy and Regenerative Medicine, King’s College LondonSt John’s Institute of Dermatology, King’s College London and Guy’s and St Thomas’ NHS Foundation TrustCenter of Gene Therapy and Regenerative Medicine, King’s College LondonCenter of Gene Therapy and Regenerative Medicine, King’s College LondonGenomics Research Platform, King’s College London NIHR Biomedical Research CentreGenomics Research Platform, King’s College London NIHR Biomedical Research CentreBoehringer Ingelheim PharmaceuticalsSt John’s Institute of Dermatology, King’s College London and Guy’s and St Thomas’ NHS Foundation TrustSt John’s Institute of Dermatology, King’s College London and Guy’s and St Thomas’ NHS Foundation TrustDepartment of Medical and Molecular Genetics, King’s College LondonSt John’s Institute of Dermatology, King’s College London and Guy’s and St Thomas’ NHS Foundation TrustAbstract Biologic therapies targeting the IL-23/IL-17 axis have transformed the treatment of psoriasis. However, the early mechanisms of action of these drugs remain poorly understood. Here, we perform longitudinal single-cell RNA-sequencing in affected individuals receiving IL-23 inhibitor therapy. By profiling skin at baseline, day 3 and day 14 of treatment, we demonstrate that IL-23 blockade causes marked gene expression shifts, with fibroblast and myeloid populations displaying the most extensive changes at day 3. We also identify a transient WNT5A+/IL24+ fibroblast state, which is only detectable in lesional skin. In-silico and in-vitro studies indicate that signals stemming from these WNT5A+/IL24+ fibroblasts upregulate multiple inflammatory genes in keratinocytes. Importantly, the abundance of WNT5A+/IL24+ fibroblasts is significantly reduced after treatment. This observation is validated in-silico, by deconvolution of multiple transcriptomic datasets, and experimentally, by RNA in-situ hybridization. These findings demonstrate that the evolution of inflammatory fibroblast states is a key feature of resolving psoriasis skin.https://doi.org/10.1038/s41467-024-44994-w |
| spellingShingle | Luc Francis Daniel McCluskey Clarisse Ganier Treasa Jiang Xinyi Du-Harpur Jeyrroy Gabriel Pawan Dhami Yogesh Kamra Sudha Visvanathan Jonathan N. Barker Catherine H. Smith Francesca Capon Satveer K. Mahil Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade Nature Communications |
| title | Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade |
| title_full | Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade |
| title_fullStr | Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade |
| title_full_unstemmed | Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade |
| title_short | Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade |
| title_sort | single cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by il 23 blockade |
| url | https://doi.org/10.1038/s41467-024-44994-w |
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