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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
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Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis

Quan Qiu1, Ze Zheng, Lin Chang

  • 1Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

The EMBO Journal
|August 15, 2013
PubMed

Insights

In rheumatoid arthritis, inositol-requiring enzyme 1α (IRE1α) drives inflammation by promoting cytokine production. Inhibiting IRE1α reduced joint inflammation in mouse models, highlighting its potential as a therapeutic target.

Area of Science:

  • Immunology
  • Molecular Biology
  • Rheumatology

Background:

  • Rheumatoid arthritis (RA) involves macrophages releasing inflammatory mediators.
  • Toll-like receptor (TLR)-mediated signaling in macrophages drives cytokine production in RA.
  • The unfolded protein response (UPR) transducer, inositol-requiring enzyme 1α (IRE1α), is implicated in inflammatory processes.

Purpose of the Study:

  • To investigate the role of IRE1α in macrophage activation and inflammatory cytokine production in rheumatoid arthritis.
  • To explore the regulatory mechanisms of IRE1α activation in response to TLR signaling.
  • To evaluate IRE1α as a potential therapeutic target for inflammatory arthritis.

Main Methods:

  • Analysis of IRE1α activation in macrophages from RA patients' synovial fluid.
  • Utilizing myeloid-specific IRE1α knockout mice to assess its role in inflammatory arthritis.
  • Employing an IRE1α-specific inhibitor (4U8C) in mouse models of joint inflammation.
  • Investigating the interaction between TRAF6, PP2A, and IRE1α in TLR-mediated signaling.

Main Results:

  • Macrophages from RA patients showed increased IRE1α activation.
  • Myeloid-specific deletion of IRE1α protected mice from inflammatory arthritis.
  • Treatment with the IRE1α inhibitor 4U8C reduced joint inflammation in mice.
  • IRE1α deficiency impaired TLR-induced pro-inflammatory cytokine production in macrophages and neutrophils.
  • TRAF6-mediated ubiquitination of IRE1α was identified as a key mechanism for its activation, preventing inhibition by PP2A.

Conclusions:

  • IRE1α plays a critical role in regulating TLR-induced pro-inflammatory cytokine production.
  • The TRAF6-IRE1α axis is a novel regulatory pathway in inflammatory responses.
  • IRE1α represents a promising therapeutic target for managing inflammatory arthritis.

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