1. Academic Validation
  2. Activation of innate immunity by 14-3-3 ε, a new potential alarmin in osteoarthritis

Activation of innate immunity by 14-3-3 ε, a new potential alarmin in osteoarthritis

  • Osteoarthritis Cartilage. 2020 May;28(5):646-657. doi: 10.1016/j.joca.2020.03.002.
M Millerand 1 L Sudre 1 M Nefla 1 F Pène 2 C Rousseau 2 A Pons 1 A Ravat 1 G André-Leroux 3 S Akira 4 T Satoh 4 F Berenbaum 5 C Jacques 1
Affiliations

Affiliations

  • 1 Sorbonne Université, INSERM (UMR_S938) and Labex Transimmunom, Paris, France.
  • 2 Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris France.
  • 3 MaIAGE, INRA, Université Paris-Saclay, 78350 Jouy-en-Josas, France.
  • 4 Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan.
  • 5 Sorbonne Université, INSERM (UMR_S938) and Labex Transimmunom, Paris, France; Sorbonne Université, Department of Rheumatology, AP-HP, Hôpital Saint-Antoine, and Labex Transimmunom, Paris, France. Electronic address: francis.berenbaum@sat.aphp.fr.
Abstract

Objective: The innate immune system plays a central role in osteoarthritis (OA). We identified 14-3-3ε as a novel mediator that guides chondrocytes toward an inflammatory phenotype. 14-3-3ε shares common characteristics with alarmins. These endogenous molecules, released into extracellular media, are increasingly incriminated in sustaining OA inflammation. Alarmins bind mainly to Toll-like Receptor 2 (TLR2) and TLR4 receptors and polarize macrophages in the synovium. We investigated the effects of 14-3-3ε in joint cells and tissues and its interactions with TLRs to define it as a new alarmin involved in OA.

Design: Chondrocyte, synoviocyte and macrophage cultures from murine or OA human samples were treated with 14-3-3ε. To inhibit TLR2/4 in chondrocytes, blocking Antibodies were used. Moreover, chondrocytes and bone marrow macrophage (BMM) cultures from knockout (KO) TLRs mice were stimulated with 14-3-3ε. Gene expression and release of inflammatory mediators [interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNFα)] were evaluated via reverse transcription quantitative polymerase chain reaction (RT-qPCR) and ELISA.

Results: In vitro, 14-3-3ε induced gene expression and release of IL6 and MCP1 in the treated cells. The inflammatory effects of 14-3-3ε were significantly reduced following TLRs inhibition or in TLRs KO chondrocytes and BMM.

Conclusions: 14-3-3ε is able to induce an inflammatory phenotype in synoviocytes, macrophages and chondrocytes in addition to polarizing macrophages. These effects seem to involve TLR2 or TLR4 to trigger innate immunity. Our results designate 14-3-3ε as a novel alarmin in OA and as a new target either for therapeutic and/or prognostic purposes.

Keywords

14-3-3 ε; Alarmin; Innate immunity; Osteoarthritis; Synovitis; TLR.

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