TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages.
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 IRE1alpha 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 IRE1alpha 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.
Martinon
Fabio
F
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
Chen
Xi
X
Lee
Ann-Hwee
AH
Glimcher
Laurie H
LH
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005604:Francisella tularensis / Q000276:immunology* / Q000472:pathogenicity; D007113:Immunity, Innate; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019154:Protein Splicing / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology; D014406:Tularemia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D000071717:X-Box Binding Protein 1
D016207:Cytokines; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D055666:Lipopeptides; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; C508075:Pam(3)CSK(4) peptide; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D048029:TNF Receptor-Associated Factor 6; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D014415:Tunicamycin; D051742:Transcription Factor CHOP; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases