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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice

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Glycoprotein 96 perpetuates the persistent inflammation of rheumatoid arthritis

Qi-Quan Huang1, Renee E Koessler, Robert Birkett

  • 1Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Arthritis and Rheumatism
|July 11, 2012
PubMed
Abstract

Insights

Endogenous gp96 acts as a Toll-like receptor-2 ligand in rheumatoid arthritis (RA), driving macrophage activation. Neutralizing gp96 ameliorated joint inflammation in a mouse model, suggesting a therapeutic target.

Area of Science:

  • Immunology
  • Rheumatology
  • Molecular Biology

Background:

  • Persistent macrophage activation is a hallmark of rheumatoid arthritis (RA), but the underlying mechanisms remain unclear.
  • Heat shock protein gp96 is implicated in immune responses, but its specific role in RA pathogenesis is not fully understood.

Purpose of the Study:

  • To investigate the contribution of endogenous gp96 to Toll-like receptor (TLR)-mediated macrophage activation in RA.
  • To explore gp96 as a potential therapeutic target for RA.

Main Methods:

  • Activation of macrophages and HEK-TLR-2/4 cells using RA synovial fluid.
  • Inhibition of activation using neutralizing antibodies against TLR-2, TLR-4, and gp96.
  • Assessment of gp96 expression and its role in a K/BxN serum transfer-induced mouse arthritis model.

Main Results:

  • RA synovial fluid activated macrophages and HEK-TLR-2/4 cells.
  • Neutralizing anti-gp96 antibodies suppressed RA synovial fluid-induced macrophage and TLR-2 activation, particularly at high gp96 concentrations.
  • Neutralization of cell surface gp96 inhibited TNFα expression, and anti-gp96 treatment reduced joint inflammation in mice.

Conclusions:

  • Endogenous gp96 functions as a TLR-2 ligand in RA, contributing to macrophage activation.
  • The TLR-2 pathway, modulated by gp96, represents a promising therapeutic target for rheumatoid arthritis.

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