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

• Published in: Frontiers in immunology Vol. 14; p. 1191782
• Main Authors: Navarro-Compán, Victoria, Puig, Luis, Vidal, Silvia, Ramírez, Julio, Llamas-Velasco, Mar, Fernández-Carballido, Cristina, Almodóvar, Raquel, Pinto, José Antonio, Galíndez-Aguirregoikoa, Eva, Zarco, Pedro, Joven, Beatriz, Gratacós, Jordi, Juanola, Xavier, Blanco, Ricardo, Arias-Santiago, Salvador, Sanz Sanz, Jesús, Queiro, Rubén, Cañete, Juan D.
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 04.08.2023
• Subjects: Arthritis, Psoriatic; Chronic Disease; Hidradenitis Suppurativa; Humans; IL-17A; IL-17F; IL-23; Immunity, Innate; Immunology; Inflammation; Interleukin-17; Interleukin-23; Lymphocytes; MAIT cells; Psoriasis; spondyloarthritis; Th17 cells; spondyloarthritis; γδ T cells; IL-17F; IL-17A; MAIT cells; psoriasis; IL-23; Th17 cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1191782

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.