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

Cole, S. et al. (2023) Differential regulation of IL-17A and IL-17F via STAT5 contributes to psoriatic disease. Journal of Allergy and Clinical Immunology, 152(3), pp. 783-798. (doi: 10.1016/j.jaci.2023.03.035) (PMID:37244461)

Abstract

Background: IL-17A has 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. Recent 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: To characterize 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 ChIP-seq and RNA-seq. 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 two isoforms influenced by pro-inflammatory 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 two genes. Functionally, higher IL17F expression was linked to greater cell proliferation. Conclusion: Our data suggest 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.

• Item Type: Articles
• Additional Information: Funded by UCB Pharma.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cole, Mr John and Goodyear, Professor Carl
• Authors: Cole, S., Manghera, A., Burns, L., Barrett, J., Yager, N., Rhys, H., Skelton, A., Cole, J., Goodyear, C. S., Griffiths, M., Baeten, D., Bertolini, M., Shaw, S., Al-Mossawi, H., and Maroof, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Allergy and Clinical Immunology
• Publisher: Elsevier
• ISSN: 0091-6749
• ISSN (Online): 1097-6825
• Published Online: 25 May 2023