Abstract
Sensors of pathogens, such as Toll-like receptors (TLRs), detect microbes to activate transcriptional programs that orchestrate adaptive responses to specific insults. Here we report that TLR4 and TLR2 specifically activated the endoplasmic reticulum (ER) stress sensor kinase IRE1α and its downstream target, the transcription factor XBP1. Previously described ER-stress target genes of XBP1 were not induced by TLR signaling. Instead, TLR-activated XBP1 was required for optimal and sustained production of proinflammatory cytokines in macrophages. Consistent with that finding, activation of IRE1α by ER stress acted in synergy with TLR activation for cytokine production. Moreover, XBP1 deficiency resulted in a much greater bacterial burden in mice infected with the TLR2-activating human intracellular pathogen Francisella tularensis. Our findings identify an unsuspected critical function for XBP1 in mammalian host defenses.
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Acknowledgements
We thank M. Greenblatt, M. Wein, V. Lazarevic and C.Hetz for comments on the manuscript; D. Malhotra for assistance with the experiments in Figures 3 and 4; A. Bolm for technical assistance; G. Chu for analysis of liver histology, V. Lazarevic, I. Kramnik and R. Pollack for help with the F. tularensis aerosol set-up; S. Akira (Osaka University) and D. Goldstein (Yale University) for MyD88-deficient mice; R. Medzhitov (Yale University) for TIRAP-knockout mice; K. Mori (Kyoto University) for antibody to ATF6α (anti-ATF6α); J. Tschopp (University of Lausanne) for anti-pro-IL-1β; John Patterson (MannKind) for the active recombinant IRE1α fragment; and the Broad Institute for reagents. Supported by the National Institutes of Health (AI32412 and AI56296), the Ragon Institute of MGH, MIT and Harvard (L.H.G.), the American Heart Association (A.-H.L.), the Leukemia and Lymphoma Society (X.C.) and the Human Frontier Science Program (F.M.).
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F.M. and L.H.G. designed the research; F.M. and X.C. did the experiments; A.-H.L. contributed critical reagents; F.M., X.C., A.-H.L. and L.H.G. analyzed the results; F.M. and X.C. made the figures; and F.M. and L.H.G wrote the paper.
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L.H.G. holds equity in and is on the corporate board of directors of Bristol-Myers Squibb.
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Martinon, F., Chen, X., Lee, AH. et al. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol 11, 411–418 (2010). https://doi.org/10.1038/ni.1857
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DOI: https://doi.org/10.1038/ni.1857