Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

Abstract

Type I IFN are strongly induced upon engagement of certain pattern recognition receptors by microbial products, and play key roles in regulating innate and adaptive immunity. It has become apparent that the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR), in addition to restoring ER homeostasis, also influences the expression of certain inflammatory cytokines. However, the extent to which UPR signaling regulates type I IFN remains unclear. Here we show that cells undergoing a UPR respond to TLR4 and TLR3 ligands, and intracellular dsRNA, with log-fold greater IFN-b induction. This synergy is not dependent on autocrine type I IFN signaling, but unexpectedly requires the UPR transcription factor X-box binding protein 1 (XBP-1). Synergistic IFN-b induction also occurs in HLA-B27/human b 2 m-transgenic rat macrophages exhibiting a UPR as a consequence of HLA-B27 up-regulation, where it correlates with activation of XBP-1 splicing. Together these findings indicate that the cellular response to endogenous 'danger' that disrupts ER homeostasis is coupled to IFN-b induction by XBP-1, which has implications for the immune response and the pathogenesis of diseases involving the UPR.Key words: HLA-B27 Á Interferons Á Protein misfolding Á Unfolded protein response IntroductionInitially identified as antiviral cytokines, type I IFN (IFN-a/b) are now recognized to have diverse immunoregulatory effects activating macrophages and NK cells, promoting T cell survival and dendritic cell (DC) maturation, and increasing the production of Th1-polarizing cytokines to mediate innate and adaptive immune responses [1]. Type I IFN also exert biological effects at low and even constitutive levels of expression [2]. For example, weak IFN-b-mediated signaling augments IFN-a/b induction in response to LPS through positive feedback involving autocrine/ paracrine up-regulation of IFN regulatory factor (IRF)7. In addition, low levels of IFN-a/b prime cells to respond to IFN-c and IL-6 by providing a phosphorylated type I IFN receptor 'niche' for commonly used signaling molecules in proximity to other cytokine receptor complexes [3,4]. Mice deficient in IFN-b are more susceptible to viral infection, have lower numbers of macrophages and mature B cells, and exhibit reduced bone mass [5], as IFN-b is a positive regulator of bone formation through inhibition of osteoclast differentiation [6]. Thus, even constitutive levels of this cytokine are important in osteo-immune homeostasis.IFN-b is produced by most cell types upon viral infection, and in large amounts by macrophages and DC, following engagement of pattern recognition receptors (PRR) by conserved molecular structures referred to as pathogen-associated molecular patterns [7, 8]. PRR that mediate IFN-b induction include cell surface TLR4 and endosomal TLR3 for LPS and dsRNA, respectively [9]. In both instances increased IFN-b gene transcription occurs via TLR/IL-1R domain-containing adapter inducing IFN-b (TRIF)-dependent IRF3 and NF-jB activation. PRR in the retinoic ...

HLA-B27 Misfolding and Spondyloarthropathies

“…In the gastrointestinal tract, a low level immune response to bacterial colonization could result in increased expression of IFNs (Type I and/or Type II), perhaps via innate immune stimuli (IFN-b) and/or NK cell activation (IFN-γ). This would result in upregulation of class I expression and, in cells expressing in BM macrophages undergoing a UPR, either due to HLA-B27 upregulation or in cells treated with pharmacologic agents (tunicamycin or thapsigargin) that cause ER stress, 86 consistent with a previous report of low-level induction in tunicamycin-treated fibroblasts. 87 IFN-b has well-recognized autocrine effects at low concentrations, [88][89][90] and thus UPR-induced IFN-b may have immunological consequences including a pro-survival effect on macrophages.…”

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

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Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

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