Out of the shadow of interleukin-17A: the role of interleukin-17F and other interleukin-17 family cytokines in spondyloarthritis

PURPOSE OF REVIEW: The last decade has witnessed tremendous advances in revealing an important role for the interleukin (IL)-17 cytokine family in the pathogenesis of spondyloarthritis (SpA). Although most attention has been focused on IL-17A, a potential role of other IL-17 family members in inflammation and tissue remodelling is emerging. Herein, I review recent studies covering the role of IL-17B-F cytokines in the pathogenesis of SpA. RECENT FINDINGS: Several recent studies provided new insights into the cellular source, regulation and function of IL-17F. IL-17F/IL-17A expression ratio is higher in psoriatic skin compared to SpA synovitis. IL-17F-expressing T cells produce different proinflammatory mediators than IL-17A-expressing cells, and IL-17F and IL-17A signal through different receptor complex. Dual IL-17A and IL-17F neutralization resulted in greater suppression of downstream inflammatory and tissue remodelling responses. Furthermore, there is additional evidence of IL-23-independent IL-17 production. In contrast to IL-17A, IL-17F and IL-17C, which play proinflammatory roles in skin and joint inflammation, an anti-inflammatory function is proposed for IL-17D. An increase in IL-17E is associated with subclinical gut microbiome alterations after anti-IL-17A therapy in SpA patients. SUMMARY: IL-17 family cytokines may act as agonists or antagonists to IL-17A contributing in concert to local inflammatory responses. Understanding their function and identifying their cellular sources, and molecular mechanisms driving their expression will be the key to designing rational therapies in SpA.