The paradigm of IL-23-independent production of IL-17F and IL-17A and their role in chronic inflammatory diseases

Abstract

Interleukin-17 family (IL-17s) comprises six structurally related members (IL-17A to IL-17F); sequence homology is highest between IL-17A and IL-17F, displaying certain overlapping functions. In general, IL-17A and IL-17F play important roles in chronic inflammation and autoimmunity, controlling bacterial and fungal infections, and signaling mainly through activation of the nuclear factor-kappa B (NF-κB) pathway. The role of IL-17A and IL-17F has been established in chronic immune-mediated inflammatory diseases (IMIDs), such as psoriasis (PsO), psoriatic arthritis (PsA), axial spondylarthritis (axSpA), hidradenitis suppurativa (HS), inflammatory bowel disease (IBD), multiple sclerosis (MS), and asthma. CD4⁺ helper T cells (Th17) activated by IL-23 are well-studied sources of IL-17A and IL-17F. However, other cellular subtypes can also produce IL-17A and IL-17F, including gamma delta (γδ) T cells, alpha beta (αβ) T cells, type 3 innate lymphoid cells (ILC3), natural killer T cells (NKT), or mucosal associated invariant T cells (MAIT). Interestingly, the production of IL-17A and IL-17F by innate and innate-like lymphocytes can take place in an IL-23 independent manner in addition to IL-23 classical pathway. This would explain the limitations of the inhibition of IL-23 in the treatment of patients with certain rheumatic immune-mediated conditions such as axSpA. Despite their coincident functions, IL-17A and IL-17F contribute independently to chronic tissue inflammation having somehow non-redundant roles. Although IL-17A has been more widely studied, both IL-17A and IL-17F are overexpressed in PsO, PsA, axSpA and HS. Therefore, dual inhibition of IL-17A and IL-17F could provide better outcomes than IL-23 or IL-17A blockade.

Keywords: IL-17A; IL-17F; IL-23; MAIT cells; Th17 cells; psoriasis; spondyloarthritis; γδ T cells.

Figure 1

IL-17 receptor family (IL-17Rs), their ligands and downstream signaling pathways. IL-17Rs are classified in “short” and “tall” according to their extracellular domains (ECD). “Short” receptors (IL-17RA, IL-17RB, and IL-17RD) present a two-domains ECD and a disordered linker near the cytoplasmic membrane with a proline-rich motif, and “tall” receptors (IL-17RC and IL-17RE) have a larger ECD with two additional domains (52). IL-17A and IL-17F homodimers and IL-17A/IL-17F heterodimers bind to IL-17RA/C receptors leading to the recruitment of the nuclear factor-kappa B (NF-κB) activator 1 (Act1) by homotypic interactions between both SEFIR (similar expression to fibroblast growth factor genes) domains. Once the complex is formed other signaling molecules (TNF receptor-associated factor [TRAF]6, TRAF2, and TRAF5) are recruited to fully activate downstream signaling pathways. Bold arrows represent a preferential binding.

Figure 2

T_H17 cell-intrinsic autocrine loop triggered by IL-17A [Figure adapted from Chong et al., 2020 (61)]. (A) IL-17A binds to IL-17RA/IL-17RC receptor and activates NF-κB inducing the expression of IL-24, which in turn inhibits NF-κB leading to the repression of other T_H17 signature cytokines (such as IL-17F and GM-CSF). (B) Blockade of IL-17A breaks the autocrine loop allowing NF-κB signaling and therefore, favoring IL-17F and GM-CSF expression.

Figure 3

Major lymphocytes populations secreting IL-17A and IL-17F. [Figure adapted from Veldhoen, 2017 (60)]. Major transcription factor associated with these cells are RORγt, and some shared surface receptors include CCR6 and IL-23R.

Figure 4

CD4+ helper T cells differentiation routes. [Figure adapted from Ruiz de Morales et al., 2020 (5)]. CD4⁺ helper T cells (Th0) differentiate into effector T cell subsets (Th1, Th2, or Th17) and regulatory T cells (T_Reg) with specific signal transduction mechanisms, transcription factors, and cytokine profiles for each cell lineage. IL-12 and IFNγ are critical cytokines initiating the downstream signaling cascade to develop Th1 cells, the T-box transcription factor (T-bet) is the master regulator for its differentiation, and mainly secrete IFNγ and IL-2 (116). For Th2 lineage development, IL-4 and IL-2 are crucial cytokines and GATA3 is the master regulator transcription factor. Among their key effector cytokines are IL-4, IL-5, and IL-13. T_Reg cells are generated after antigen stimulation under TGF-β and IL-2 presence, express the Foxp3 transcription factor and have a role in maintaining immune homeostasis through their main effector cytokines TGF-β and IL-10. IL-1β, IL-6, or IL-21 are required for the differentiation of Th17 cells, which express RORgt and secrete IL-17s (115, 117). TGF-β and IL-6 exposure sustained the differentiation of non-pathogenic Th17 cells (co-expression of T-Bet), whereas IL-23 induce a pathogenic profile (co-expression of Foxp3). Newly described Th17/Th2 cells express markers of both CD4⁺ T cells (CD161 and RORγt, and GATA3) and produce IL-4 and IL-17. This phenotype is also considered pathogenic (118).