Differential regulation of IL-17A and IL-17F via STAT5 contributes to psoriatic disease

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 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. (J Allergy Clin Immunol 2023;152:783-98.)

Automated summary

This study characterizes the regulation of IL-17A and IL-17F in psoriatic disease, showing that IL-17F is elevated preferentially over IL-17A and that each isoform is expressed in distinct cell populations. The study also reveals the plasticity of IL-17A and IL-17F expression, influenced by proinflammatory signaling and anti-inflammatory drugs. Higher IL-17F expression is linked to increased cell proliferation, suggesting the importance of neutralizing both IL-17A and IL-17F in inhibiting IL-17-driven pathology.