Toll-like receptor activation of XBP1 regulates innate immune responses in macrophages

By Fabio Martinon, X. Chen, Ann-Hwee Lee, Laurie H. Glimcher. Nature Immunology, 2010

944 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Endocrinology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/7e4fc71b1ab5640dab7515cf407d4085d712f246

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Citations in the corpus

The unfolded protein response: controlling cell fate decisions under ER stress and beyond (2012, background): “Further studies indicate that pro-inflammatory stimuli that engage certain Toll-like receptors (TLRs), including lipopolysaccharide (LPS), specifically trigger XBP1 mRNA splicing to enhance the transcription of pro-inflammatory cytokines, such as IL-6 (Ref”
Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS) (2011, background): “, 2010), macrophages undergoing ER stress can exhibit increased XBP-1 splicing without activation of many ER stress–induced genes (Martinon et al., 2010).”
Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer (2017, positive): “XBP1 expression in macrophages was necessary for optimal production of IL-6 in response to Tolllike receptor (TLR) agonists, and mice devoid of XBP1 showed increased bacterial burden in models of systemic Francisella tularensis infection (Martinon et al., 2010).”
The impact of the unfolded protein response on human disease (2012, background): “This TLR-dependent Xbp1 mRNA splicing is required for maximal production of proinflammatory cytokines, such as interleukin 6 in macrophages (Martinon et al., 2010).”
ER stress-induced cell death mechanisms. (2013, background): “IRE1α can be phosphorylated by signals downstreamof Toll-like receptors (TLRs) to induceXBP-1mRNA splicing and support production of proinflammatory cytokines in macrophages [75].”
The Cellular Biology of Macrophages in Atherosclerosis (2011, positive): “, 2010a), and ER stress-signaling pathways active in advanced plaque progression are essential for macrophage cytokine production during host defense (Martinon et al., 2010).”
Intestinal homeostasis and its breakdown in inflammatory bowel disease (2011, background): “Recent studies have also reported interactions between TLR and ER stress pathways, although both inhibition and activation of distinct arms of the UPR have been observed after TLR stimulatio”
Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis (2010, background): “(7) Only recently has it been demonstrated that TLR2 and TLR4 activate IRE1 and its downstream target XBP1.(114) 1842 TILG AND MOSCHEN HEPATOLOGY, November 2010”