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

白细胞介素17 生物 染色质免疫沉淀 细胞因子 染色质 免疫学 白细胞介素22 白细胞介素 基因亚型 基因表达 细胞生物学 基因 遗传学 发起人
作者
Suzanne Cole,Avneet Manghera,Lachrissa A. Burns,Janine Barrett,Nicole Yager,Hefin Rhys,Andrew Skelton,John J. Cole,Carl S. Goodyear,Meryn Griffiths,Dominique Baeten,Marta Bertolini,Stevan Shaw,Hussein Al‐Mossawi,Asher Maroof
出处
期刊:The Journal of Allergy and Clinical Immunology [Elsevier]
卷期号:152 (3): 783-798 被引量:13
标识
DOI:10.1016/j.jaci.2023.03.035
摘要

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.We characterized the regulation of IL-17A and IL-17F in psoriatic disease.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.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.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.
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