Elsevier

Journal of Autoimmunity

Volume 50, May 2014, Pages 59-66
Journal of Autoimmunity

TLR dependent XBP-1 activation induces an autocrine loop in rheumatoid arthritis synoviocytes

https://doi.org/10.1016/j.jaut.2013.11.002Get rights and content
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Highlights

  • sXBP1 is upregulated in PBMC from patients with active RA.

  • TLR2 and TLR4 mediated sXBP1 activation in synovial fibroblasts.

  • SNAPIN-induced cytokine production is dependent on sXBP1.

  • Proinflammatory cytokines cause XBP1 activation in synovial fibroblasts.

Abstract

X-box binding protein 1 (XBP1) is a central regulator of the endoplasmic reticulum (ER) stress response. It is induced via activation of the IRE1 stress sensor as part of the unfolded protein response (UPR) and has been implicated in several diseases processes. XBP1 can also be activated in direct response to Toll-like receptor (TLR) ligation independently of the UPR but the pathogenic significance of this mode of XBP1 activation is not well understood. Here we show that TLR-dependent XBP1 activation is operative in the synovial fibroblasts (SF) of patients with active rheumatoid arthritis (RA). We investigated the expression of ER stress response genes in patients with active RA and also in patients in remission. The active (spliced) form of (s)XBP1 was significantly overexpressed in the active RA group compared to healthy controls and patients in remission. Paradoxically, expression of nine other ER stress response genes was reduced in active RA compared to patients in remission, suggestive of a UPR-independent process. However, sXBP1 was induced in SF by TLR4 and TLR2 stimulation, resulting in sXBP1-dependent interleukin-6 and tumour necrosis factor (TNF) production.

We also show that TNF itself induces sXBP1 in SF, thus generating a potential feedback loop for sustained SF activation. These data confirm the first link between TLR-dependent XBP1 activation and human inflammatory disease. sXBP1 appears to play a central role in this process by providing a convergence point for two different stimuli to maintain activation of SF.

Keywords

Rheumatoid arthritis (RA)
Unfolded protein response (UPR)
sXBP1
Toll-like receptor (TLR)

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This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).