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

Abstract

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 (ζ) has a role in T-cell polarization and interleukin (IL)-17A signal transduction. Here, we demonstrate 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. Arthritic 14-3-3ζ KO animals showed an increase in bone loss and immune cell infiltration in synovial joints. Induction of arthritis coincided with the loss of anti-14-3-3ζ antibodies; however, rescue experiments to supplement the 14-3-3ζ antibody by passive immunization did not suppress arthritis. Instead, 14-3-3ζ immunization during the presymptomatic phase resulted in significant suppression of arthritis in both wild-type and 14-3-3ζ KO animals. Mechanistically, 14-3-3ζ KO rats exhibited elevated inflammatory gene signatures at the messenger RNA and protein levels, particularly for IL-1β. Furthermore, the immunization with recombinant 14-3-3ζ protein suppressed IL-1β levels, significantly increased anti-14-3-3ζ antibody levels and collagen production, and preserved bone quality. The 14-3-3ζ protein increased collagen expression in primary rat mesenchymal cells. Together, our findings indicate that 14-3-3ζ causes immune suppression and extracellular remodeling, which lead to a previously unrecognized IA-suppressive function.

A broad look into the future of rheumatoid arthritis

“…Recently, passive immunization with the protein 14-3-3zeta (ζ), that is involved in T-cell polarization and IL-17A signal transduction has been shown to suppress arthritis in 14-3-3ζ knockout inflammatory arthritis rat-models by the suppression of IL-1beta levels and increased collagen production. 33…”

“…Recently, passive immunization with the protein 14-3-3zeta (ζ), that is involved in T-cell polarization and IL-17A signal transduction has been shown to suppress arthritis in 14-3-3ζ knockout inflammatory arthritis ratmodels by the suppression of IL-1beta levels and increased collagen production. 33 Another approach is the polarization of T helper cell 2 (Th2) by the peptide vaccine CEL-4000 which utilizes an MHC class-II specific ligand to activate regulatory responses. 34 DEN-181 uses liposomal technology to inject collagen II as a liposome-encapsulated antigen together with calcitriol in patients with ACPApositive RA.…”

KIF1C and new Huntingtin-interacting protein 1 binding proteins regulate rheumatoid arthritis fibroblast-like synoviocytes’ phenotypes

“…14-3-3eta (YWHAH) has been identified in the serum and synovial fluid of patients with RA, and levels correlate with disease severity and activity ( 47 – 49 ). 14-3-3zeta (YWHAZ) protein was shown to have a suppressive activity in arthritis in rats, and its deletion increased disease severity ( 50 ). 14-3-3gamma (YWHAG) and 14-3-3eta (YWHAH) were among the proteins co-immunoprecipitated with anti-HIP1, and their knockdown significantly reduced FLS adhesion and invasion.…”

Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis

“…Our stability and safety data suggest that these nanoformulations are safe and could be licensed for the pilot patient trials. Finally, 14-3-3 zeta (an autoantigen) has been shown to suppress inflammatory arthritis, 79 suggesting its potential as a potential vaccine candidate. Its antigenic potential should be however studied in the animal model(s).…”