Small anti-viral compounds activate immune cells via the TLR7 MyD88–dependent signaling pathway

Hemmi, Hiroaki; Kaisho, Tsuneyasu; Takeuchi, Osamu; Sato, Shintaro; Sanjo, Hideki; Hoshino, Katsuaki; Horiuchi, Takao; Tomizawa, Hideyuki; Takeda, Kiyoshi; Akira, Shizuo

doi:10.1038/ni758

Cited by 2,215 publications

(1,709 citation statements)

References 46 publications

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“…Several studies using naturally mutant mice have implicated wild-type TLR4 in successful host defense against a variety of Gram-negative bacteria. The prototypic example is the C3H/HeJ mouse strain that is exquisitely sensitive to progressive, overwhelming infection by Salmonella typhimurium (LD 50 o2 colony forming units (CFU)) compared to closely related strains (LD 50 42 Â 10 3 CFU). 52 This strain was also shown to be hyporesponsive to the proinflammatory properties of purified LPS, and both phenotypes were mapped to a single genetic locus on chromosome 4 initially termed Lps.…”

Section: Gram-negative Bacteriamentioning

confidence: 99%

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Toll-like receptors and their role in experimental models of microbial infection

2003

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Effective host defense against microbial infection depends upon prompt recognition of pathogens, activation of immediate containment measures, and ultimately the generation of a specific and definitive adaptive immune response. The innate immune system of the host is responsible for providing constant surveillance against infection; when confronted by pathogens it deploys a series of rapidly acting antimicrobial effectors while simultaneously instructing the adaptive immune system as to the nature and context of the infectious threat. Pathogen recognition and activation of innate immunity is mediated by members of the Toll-like receptor (TLR) family through detection of conserved microbial structures that are absent from the host. Experimental models of infection using TLR-deficient mice, as well as limited human studies, have clearly demonstrated the critical role of TLRs in host defense against most major groups of mammalian pathogens.

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Section: Gram-negative Bacteriamentioning

confidence: 99%

“…Recent reports also suggest that mouse TLR7 and human TLR7 and TLR8 may participate in antiviral host defense, based on the observation that small antiviral imidazoquinoline compounds are capable of stimulating cellular activation through these receptors. 50,51 …”

Section: Viral Infectionmentioning

confidence: 99%

Toll-like receptors and their role in experimental models of microbial infection

2003

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“…Both CpG-A and CpG-B have been shown to activate PDC via TLR9 [23]. Upon phagocytosis PDC lyse microorganisms in phagolysosomes, where microbial DNA interacts with and activates TLR9 derived from the endoplasmic reticulum [24].…”

Section: Introductionmentioning

confidence: 99%

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

et al. 2005

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Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the bestcharacterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. IntroductionDendritic cells (DC) are potent antigen-presenting cells bridging the innate and adaptive immune responses. To date, two subsets of DC have been identified in humans: myeloid DC and plasmacytoid DC (PDC), the latter also referred to as type I interferon (IFN-a)-producing cells [1][2][3][4][5][6]. PDC recognize viral or bacterial DNA patterns, consisting of unmethylated CpG motifs in the context of species-dependent surrounding sequences (CpG) [7]. As a consequence they produce, within a few hours, large amounts of . Based on their ability to induce IFN-a secretion by PDC, two types of CpG have been described: CpG 2216 (CpG-A), which induces high amounts of IFN-a, and CpG 2006 (CpG-B), which promotes survival, maturation and migration of PDC to the lymph nodes, but induces lower amounts of . PDC sustain the priming of naive T cells and their differentiation into Th1/Th2 effectors [15][16][17] or into regulatory T cells [16,[18][19][20][21][22].Recent studies shed light on the events involved in the recognition of microbial DNA by human PDC, the only subset of human DC that expresses the Toll-like receptor 9 (TLR9) [12]. Both CpG-A and CpG-B have been shown to activate PDC via TLR9 [23]. Upon phagocytosis PDC lyse microorganisms in phagolysosomes, where microbial DNA interacts with and activates TLR9 derived from the endoplasmic reticulum [24]. TLR9 activation leads to recruitment of the MyD88 adaptor protein and phosphorylation of the IL-1R-associated kinase (IRAK). Phosphorylated IRAK associates with the adaptor molecule TNF-associated factor 6 (TRAF6) [25]. Two separate signaling pathways, JNK and NF-jB, are then activated, promoting PDC maturation and survival. IFN-a induction, an event exclusively occurring in PDC, depends on the formation of a complex consisting of MyD88, TRAF6 and the IRF7 transcription factor, as well as on TRAF6-dependent ubiquitination [26].The events that determine the outcome of the interaction of PDC with T cells, and in particular the induction of effector or regulatory immune responses, are poorly characterized. Environmental signals that Here we report that HMGB1 is exported from the nucleus of PDC upon selective engagement of TLR9 an...

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“…1). Through this mechanism, TLR7 may receive [24][25][26][27] , several studies have indicated nonspecifi c effects of imiquimod on neurons. We have shown that imiquimod, CL075, and loxoribine restrict dendrite growth in wild-type rodent cortical and hippocampal neurons [11] .…”

Section: Endosomal Tlrs and Their Ligandsmentioning

confidence: 99%

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

2014

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The central nervous system is recognized as an immunoprivileged site because peripheral immune cells do not typically enter it. Microglial cells are thought to be the main immune cells in brain. However, recent reports have indicated that neurons express the key players of innate immunity, including Toll-like receptors (TLRs) and their adaptor proteins (Sarm1, Myd88, and Trif), and may produce cytokines in response to pathogen infection. In the absence of an immune challenge, neuronal TLRs can detect intrinsic danger signals and modulate neuronal morphology and function. In this article, we review the recent fi ndings on the involvement of TLRs and Sarm1 in controlling neuronal morphogenesis and neurodegeneration. Abnormal behaviors in TLRand Sarm1-defi cient mice are also discussed.

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Small anti-viral compounds activate immune cells via the TLR7 MyD88–dependent signaling pathway

Cited by 2,215 publications

References 46 publications

Toll-like receptors and their role in experimental models of microbial infection

Toll-like receptors and their role in experimental models of microbial infection

Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

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