Pathogenic Role of IL-17 and Therapeutic Targeting of IL-17F in Psoriatic Arthritis and Spondyloarthropathies

Abstract

The interleukin 17 (IL-17) family, a subset of cytokines consisting of IL-17A-F, plays crucial roles in host defence against microbial organisms and the development of inflammatory diseases, including psoriasis (PsO), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA). IL-17A is the signature cytokine produced by T helper 17 (Th17) cells and is considered the most biologically active form. The pathogenetic involvement of IL-17A in these conditions has been confirmed, and its blockade with biological agents has provided a highly effective therapeutical approach. IL-17F is also overexpressed in the skin and synovial tissues of patients with these diseases, and recent studies suggest its involvement in promoting inflammation and tissue damage in axSpA and PsA. The simultaneous targeting of IL-17A and IL-17F by dual inhibitors and bispecific antibodies may improve the management of Pso, PsA, and axSpA, as demonstrated in the pivotal studies of dual specific antibodies such as bimekizumab. The present review focuses on the role of IL-17F and its therapeutic blockade in axSpA and PsA.

Keywords: axial spondyloarthritis; bimekizumab; interleukin 17F; psoriasis; psoriatic arthritis; sonelokimab.

Figure 1

IL-17RA/RC signalling pathways (Figure adapted from Monin and Gaffen [3], and from Chung [4]). Homotypic interactions between the SEF/IL-17R (SEFIR) domains of the receptor and the adaptor Act1/CIKS are made possible by ligand (IL-17A/IL-17F/IL-17A/F) binding to the receptor complex. The nuclear factor kB (NF-kB) route, the CCAAT/enhancer-binding protein b (C/EBPb), and the mitogen-activated protein kinase (MAPK) pathways are all activated by the conventional IL-17 signalling pathway, which is started by Act1-induced K63 linked ubiquitination of TNF receptor associated factor 6 (TRAF6). Downstream target genes, such as those encoding proinflammatory cytokines, chemokines, and antimicrobial peptides, are then transcriptionally activated as a result. In contrast, noncanonical signalling relies on Act1 phosphorylation at amino acid 311, leading to recruitment of the RNA-binding protein HuR and formation of the TRAF2/TRAF5 complex, which sequesters the alternative splicing factor ASF/SF2 (mRNA-destabilizing) [3,4].

Figure 2

Cartoon representation of the structure of IL-17F. IL-17F is a structural homolog of proteins containing a cystine knot fold, characterized by two sets of paired β-strands (numbered 1–4) connected by disulphide linkages between strands 2 and 4, and a third disulphide bridge connecting strands 1 and 3 that is lacking in the IL-17F protomer (Figure adapted from Hymowitz [13]). Cysteine residues are represented as orange circles, disulphide linkages as dashed lines of the same colour.