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

Joshua Kim, Krista Chun, Jenna McGowan, Youjie Zhang, Piotr J. Czernik, Blair Mell, Bina Joe, Saurabh Chattopadhyay, Joseph Holoshitz, Ritu Chakravarti

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish
Article numbere2025257118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number34
DOIs
StatePublished - Aug 24 2021

Bibliographical note

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

Keywords

  • 14-3-3zeta
  • Bone loss
  • Collagen
  • Il-1beta
  • Inflammatory arthritis

ASJC Scopus subject areas

  • General

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