Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation.
Signaling by Toll-like receptors (TLRs) is central to evoking innate immunity, wherein each TLR is activated by distinct pathogen-derived agonists. It has been shown previously that TLR signaling occurs in synergy when certain TLR agonist combinations simultaneously activate immune cells. This synergism may constitute a mechanism critical to ensuring the effective activation of the immune system by multiple TLR activating molecules associated with a given pathogen; however, its underlying mechanism(s) remain unclarified. Here, we provide evidence that TLRs utilizing the MyD88 adaptor selectively cooperate with those utilizing the TRIF adaptor for synergistic induction of a set of target genes, and that this synergism is abrogated in cells lacking either MyD88 or TRIF. Moreover, we also provide evidence that this TLR synergy is mediated, at least in part, by activation of the transcription factor interferon regulatory factor 5 (IRF5). Thus, our findings offer a mechanistic insight into TLR synergy, revealing the hitherto unknown cross talk between the MyD88 and TRIF pathways for a robust TLR-mediated activation of the immune system.
Ouyang
Xinshou
X
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Tokyo, Japan.
Negishi
Hideo
H
Takeda
Rie
R
Fujita
Yasuyuki
Y
Taniguchi
Tadatsugu
T
Honda
Kenya
K
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D004269:DNA, Bacterial / Q000494:pharmacology; D000077271:Imiquimod; D050835:Interferon Regulatory Factors / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D011070:Poly I-C / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D000634:Aminoquinolines; D004269:DNA, Bacterial; D000077271:Imiquimod; D050835:Interferon Regulatory Factors; D018664:Interleukin-12; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D011070:Poly I-C; D051193:Toll-Like Receptors; C472452:CpG-DNA, E coli; C498178:Irf5 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse