14-3-3ζ: Inhibitors of inflammatory arthritis

PNAS August 24, 2021 118 (34) e2025257118; https://doi.org/10.1073/pnas.2025257118

Commentary

Inflammatory arthritis (IA) is a common disease and the inflammatory events during IA pathogenesis are well studied, but the loss of protective immunity remains unexplored.

Since previous studies have reported that 14-3-3zeta (ζ) plays a role in T-cell polarization and interleukin (IL)-17A signaling, this study shows that 14-3-3ζ knockout (KO) rats develop early-onset severe arthritis in two independent models of IA, pristane-induced arthritis and collagen-induced arthritis.

The arthritic 14-3-3ζKO animals showed bone loss and increased immune cell infiltration in synovial joints.

Although the induction of arthritis coincided with the loss of anti-14-3-3ζ antibodies, we observed that rescue experiments to compensate for 14-3-3ζ antibodies by passive immunization did not suppress arthritis.

14-3-3ζ immunization at the pre-symptomatic stage resulted in significant suppression of arthritis in both wild-type and 14-3-3ζKO animals, and mechanistically, 4-3-3ζKO rats showed elevated inflammatory gene signatures at messenger RNA and protein levels, especially for IL-1β.

Furthermore, immunization with recombinant 14-3-3ζ protein suppressed IL-1β levels, significantly increased anti-14-3-3ζ antibody levels and collagen production, and maintained bone quality.

The 14-3-3ζ protein increased collagen expression in primary rat mesenchymal cells, and this finding indicates that 14-3-3ζ causes immunosuppression and extracellular remodeling, which leads to a previously unrecognized IA-suppressive function.