Abstract
Background: IL-17A plays a pivotal pathogenic role in several immune-mediated inflammatory diseases. Despite sharing 50% sequence homology with IL-17A, the role of IL-17F remains less clear. Clinical findings suggest that dual inhibition of IL-17A and IL-17F in psoriatic disease is more efficacious than IL-17A inhibition alone, positing a pathogenic role for IL-17F. Objective: We characterized the regulation of IL-17A and IL-17F in psoriatic disease. Methods: Using both in vitro systems and lesional skin tissue from patients, we interrogated the chromosomal, transcriptional, and protein expression landscape of IL-17A+ and IL-17F+ TH17 cells. Alongside established assays such as single-cell RNA sequencing, we developed a novel cytokine-capture technique that was combined with chromatin immunoprecipitation sequencing and RNA sequencing. Results: We confirm a preferential elevation of IL-17F over IL-17A in psoriatic disease and show that expression of each isoform predominantly occurs in distinct cell populations. The expression of both IL-17A and IL-17F exhibited a high degree of plasticity, with the balance between the 2 isoforms influenced by proinflammatory signaling and by anti-inflammatory drugs such as methylprednisolone. This plasticity was reflected in a broad H3K4me3 region at the IL17A–F locus, while opposing effects of STAT5/IL-2 signaling were observed for each of the 2 genes. Functionally, higher IL17F expression was linked to greater cell proliferation. Conclusion: There are key differences in the regulation of IL-17A and IL-17F in psoriatic disease, leading to distinct inflammatory cell populations. As such, we propose that both IL-17A and IL-17F neutralization may be required to maximally inhibit IL-17–driven pathology.
Original language | English |
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Pages (from-to) | 783-798 |
Number of pages | 16 |
Journal | Journal of allergy and clinical immunology |
Volume | 152 |
Issue number | 3 |
Early online date | 2023 |
DOIs | |
Publication status | Published - Sept 2023 |
Keywords
- IL-17A
- IL-17F
- STAT5
- autoimmunity
- bimekizumab
- inflammation
- psoriasis
- psoriatic arthritis