Sci. Signal., 27 April 2010
Immunology UPR to TLR Connection
Nancy R. Gough
Science Signaling, AAAS, Washington, DC 20005, USA
Cell stress can trigger an innate immune response, as can detection of pathogens by receptors of the Toll-like receptor (TLR) family. The accumulation of unfolded proteins in the endoplasmic reticulum triggers a response called the unfolded protein response (UPR), which involves three different and parallel sensors—the kinase IRE1, the kinase PERK, and the transcription factor ATF6 (see Engel and Barton). Activation of IRE1 stimulates the cleavage and translation of the mRNA for the transcription factor XBP1, and the precursor mRNA has been found to be increased in cells responding to TLR stimulation or infection with pathogens that activate TLR signaling. Thus, Martinon et al. explored the connection between TLR signaling and XBP1 activation. Exposure of mouse macrophages to the TLR2 agonist Pam3CSK4 or the TLR4 agonist lipopolysaccharide (LPS) or infection of macrophages with the pathogens recognized by either TLR2 or TLR4 stimulated the production of mature XBP1. LPS triggered the activation of IRE1, but not that of ATF6 or PERK, and failed to stimulate increased expression of genes induced by ER stress. Indeed, the classic ER stress response caused by the glycosylation inhibitor tunicamycin was inhibited in cells exposed to LPS or Pam3CSK4, despite increased IRE1 activity and XBP1 production. Analysis of the XBP1 transcript in cells in which various components of the TLR2 or TLR4 pathway were inhibited (through genetic ablation, with short hairpin RNAs, or pharmacologically) revealed that the scaffold and ubiquitin ligase TRAF6 was required, but that activation of NF-B (nuclear factor B) or the mitogen-activated protein kinases p38 and JNK pathways was not. TRAF6 activates the NADPH oxidase NOX2, and TLR-stimulated processing of XBP1 mRNA was blocked by inhibition of NOX2 activity or NOX2 deficiency. The importance of XBP1 in the innate immune response was demonstrated by analyzing mice deficient in XBP1 (XBP1) and macrophages from these mice. Production of a subset of inflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor (TNF), ISG15 (a ubiquitin-like protein), and interferon-β (IFN-β), was impaired in XBP1 macrophages exposed to TLR4 or TLR2 agonists or in XBP1 mice exposed to Francisella tularensis (a TLR2-activating pathogen). Production of the inflammatory mediators in macrophages exposed to LPS was enhanced if the cells were also treated with tunicamycin to trigger ER stress. Finally, although survival was not affected, XBP1 mice infected with F. tularensis had a higher bacterial burden and prolonged infection compared with wild-type mice. In summary, activation of plasma membrane–localized TLRs appears to suppress the classic ER response and activates IRE1 to increase XBP1, which then serves as a transcriptional regulator of inflammatory genes.
F. Martinon, X. Chen, A.-H. Lee, L. H. Glimcher, TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11, 411–418 (2010). [PubMed]
A. Engel, G. M. Barton, Unfolding new roles for XBP1 in immunity. Nat. Immunol. 11, 365–367 (2010). [PubMed]
Citation: N. R. Gough, UPR to TLR Connection. Sci. Signal. 3, ec124 (2010).
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