From Messengers to Receptors in Psoriasis: The Role of IL-17RA in Disease and Treatment

Abstract

The paradigm of psoriasis as a Th17-driven disease has evolved in the last years towards a much deeper knowledge of the complex pathways, mechanisms, cells, and messengers involved, highlighting the crucial role played by the IL-17 family of cytokines. All IL-17 isoforms signal through IL-17R. Five subunits of IL-17R have been described to date, which couple to form a homo- or hetero-receptor complex. Characteristically, IL-17RA is a common subunit in all hetero-receptors. IL-17RA has unique structural-containing a SEFIR/TILL domain-and functional-requiring ACT-1 for signaling-properties, enabling Th17 cells to act as a bridge between innate and adaptive immune cells. In psoriasis, IL-17RA plays a key role in pathogenesis based on: (a) IL-17A, IL-17F, and other IL-17 isoforms are involved in disease development; and (b) IL-17RA is essential for signaling of all IL-17 cytokines but IL-17D, whose receptor has not been identified to date. This article reviews current evidence on the biology and role of the IL-17 family of cytokines and receptors, with focus on IL-17RA, in psoriasis and some related comorbidities, and puts them in context with current and upcoming treatments.

Keywords: IL-17; IL-17R; Th17; bimekizumab; brodalumab; ixekizumab; monoclonal antibodies; psoriasis; secukinumab.

Figure 1

IL-17 family and treatments acting on the IL-17 pathway. Illustration of the different IL-17 ligands and receptors, and scheme of the intracellular signaling cascade (using an example of the activation of the IL-17A receptor). * IL-17D is not represented as its receptor remains unidentified; neither is IL-17B for the sake of simplicity. SEFIR: SEF/IL-17 receptor; SEFEX: SEFIR extension; CBAD: C/EBPß activation domain; and TRAF: TNF-receptor associated factor. Circles mean the blocking target of each therapy: those within yellow circles blocked by Brodalumab, those within green circle blocked by Secukinumab and Ixekizumab and those within pink circle blocked by Bimekizumab. This illustration has been elaborated from information available in references [26,27,30,36].