14-3-3ζ: A suppressor of inflammatory arthritis

Inflammatory arthritis (IA) is a common disease that affects millions of individuals worldwide. Proinflammatory events during IA pathogenesis are well studied; however, loss of protective immunity remains underexplored. Earlier, we reported that 14-3-3zeta (zeta) has a role in T-cell polarization and interleukin (IL)-17A signal transduction. Here, we demonstrate that 14-3-3 zeta knockout (KO) rats develop early-onset severe arthritis in two independent models of IA, pristane-induced arthritis and collagen-induced arthritis. Arthritic 14-3-3 zeta KO animals showed an increase in bone loss and immune cell infiltration in synovial joints. Induction of arthritis coincided with the loss of anti-14-3-3 zeta antibodies; however, rescue experiments to supplement the 14-3-3 zeta antibody by passive immunization did not suppress arthritis. Instead, 14-3-3 zeta immunization during the presymptomatic phase resulted in significant suppression of arthritis in both wild-type and 14-3-3 zeta KO animals. Mechanistically, 14-3-3 zeta KO rats exhibited elevated inflammatory gene signatures at the messenger RNA and protein levels, particularly for IL-1 beta. Furthermore, the immunization with recombinant 14-3-3 zeta protein suppressed IL-1 beta levels, significantly increased anti-14-3-3 zeta antibody levels and collagen production, and preserved bone quality. The 14-3-3 zeta protein increased collagen expression in primary rat mesenchymal cells. Together, our findings indicate that 14-3-3 zeta causes immune suppression and extracellular remodeling, which lead to a previously unrecognized IA-suppressive function.

Automated summary

Inflammatory arthritis (IA) is a common disease affecting millions worldwide. 14-3-3 zeta protein plays a role in immune suppression and extracellular remodeling, leading to previously unrecognized IA-suppressive function. Immunization with recombinant 14-3-3 zeta protein can suppress IL-1 beta levels and inhibit the progression of IA.