IL-23 licenses the transition from preclinical autoimmunity to inflammatory arthritis through IL-17A-dependent mechanisms

Objectives: The mechanisms driving transition from systemic autoimmunity to clinical rheumatoid arthritis (RA) remain poorly understood. We investigated the role of interleukin-23 (IL-23) in disease transition using a murine model of experimental arthritis, complemented by human transcriptomic analyses in individuals at risk of RA and RA synovial tissue. Methods: Collagen-induced arthritis (CIA) was induced in less susceptible C57BL/6 mice and combined with sustained systemic IL-23 overexpression. Disease severity, histopathology, immune responses, and tissue gene expression were evaluated. The contribution of IL-17A was assessed using a neutralizing anti-IL-17A antibody. Expression of IL-23 pathway-related genes was assessed in whole-blood transcriptomic data from a large cohort of first-degree relatives of patients with RA (n=1080) and in an independent synovial RNA-sequencing dataset (n=218). Results: In mice, sustained IL-23 overexpression converted a mild CIA phenotype into a highly penetrant arthritis characterized by increased expression of innate inflammatory mediators, and enhanced antigen-specific production of IL-17A and IFN-{gamma}, despite unchanged collagen-specific antibody responses. Neutralization of IL-17A prevented arthritis development. In human whole blood longitudinal analyses, lower RORC and KLRB1 expression was associated with a higher risk of RA onset. KLRB1 expression was persistently lower in progressors, whereas RORC expression showed a steeper decline before diagnosis, although this difference did not remain significant after correction for multiple testing. In RA synovium, IL23R, IL23A, and CCR2 expression was increased compared with controls, while IL23R expression was higher in early than established RA. Conclusions: IL-23 acts as a critical regulator of the transition from systemic autoimmunity to inflammatory arthritis by promoting IL-17A-dependent cellular and myeloid inflammatory pathways. The change in IL-23 pathway signatures in at-risk individuals and early RA supports the translational relevance of this pathway during disease initiation.