Identification of Lps2 as a key transducer of MyD88-independent TIR signalling

Hoebe, Kasper; Du, Xin; Georgel, Philippe; Janssen, Edith M.; Tabeta, Koichi; Kim, S. O.; Goode, Jason; Lin, Pei; Mann, Navjiwan; Mudd, Suzanne; Crozat, Karine; Sovath, Sosathya; Han, Jiahuai; Beutler, Bruce

doi:10.1038/nature01889

Cited by 1,121 publications

(999 citation statements)

References 31 publications

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“…Subsequent studies identified TIR domain-containing adaptor-inducing IFN-b (TRIF), also known as TIR-containing adaptor molecule (TICAM)-1, as the key regulator of the Myd88-independent pathway. TRIF-knockout mice, or mice with a frame shift mutation resulting in a truncated form of TRIF, fail to show Myd88-independent activation of NF-kB and are non-responsive to LPS or the TLR3 ligand poly(I:C), with respect to the expression of IFN-inducible genes [20,21]. TRIF interacts directly with the TIR domain of TLR3 [22] and mediates signalling, whereas another TIR domaincontaining adaptor TRIF-related adaptor molecule (TRAM), also known as TICAM-2, acts as a bridging adaptor between TLR4 and TRIF [23].…”

Section: Myd88-dependent Signalling and Activation Of Nf-kbmentioning

confidence: 99%

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

Moynagh

2005

Trends in Immunology

290

215

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Section: Myd88-dependent Signalling and Activation Of Nf-kbmentioning

confidence: 99%

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

Moynagh

2005

Trends in Immunology

290

215

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“…Lps2, a non-functional codominant allele of Trif, was induced by N-ethyl-N-nitrosourea mutagenesis on a pure C57BL/6 mouse background [49] in the Scripps Institute animal facilities (La Jolla CA). C3H/HeN, C3H/HeJ, C57BL/10ScN, C57BL/10ScSn, C57BL/6, Trif Lps2/ Lps2 , Trif Lps2/WT , C57BL/6 Myd88 -/-, C57BL/6 Tlr4 -/-and C57BL/6/129 Trif -/-mice were bred at the MIG animal facilities (Lund, Sweden).…”

Section: Mouse Strainsmentioning

confidence: 99%

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

et al. 2006

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The mucosal host defence discriminates pathogens from commensals, and prevents infection while allowing the normal flora to persist. Paradoxically, Toll-like receptors (TLR) control the mucosal defence against pathogens, even though the TLR recognise conserved molecules like LPS, which are shared between pathogens and commensals. This study proposes a mechanism of pathogen-specific mucosal TLR4 activation, involving adhesive ligands and their host cell receptors. TLR4 signalling was activated in CD14-negative, LPS-unresponsive epithelial cells by P fimbriated, uropathogenic Escherichia coli but not by a mutant lacking fimbriae. Epithelial TLR4 signalling in vivo involved the glycosphingolipid receptors for P fimbriae and the adaptor proteins Toll/IL-1R (TIR) domain-containing adaptor inducing IFN-b (TRIF)/TRIF-related adaptor molecule (TRAM), but myeloid differentiation protein 88 (MyD88)/TIR domain-containing adaptor protein were not required for the epithelial response. Substituting the P fimbriae with type 1 fimbriae changed TLR4 signalling from the TRIF to the MyD88 adaptor pathway. In addition, the adaptor proteins and the fimbrial type were found to influence bacterial clearance. Trif -/-and Tram -/-mice remained infected with P fimbriated E. coli but cleared thetype 1 fimbriated strain, while Myd88 -/-mice became carriers of both the P and the type 1 fimbriated bacteria. Thus, TLR4 may be engaged specifically by pathogens, when the proper cell surface receptors are engaged by virulence ligands. IntroductionToll-like receptors (TLR) control the innate host defence at mucosal surfaces and yet commensals do not induce an inflammatory response at those sites. The relative inertia to the commensals is paradoxical, as the TLR recognise conserved pathogen-associated molecular patterns (PAMP), which are present on both pathogenic and commensal bacteria. Lipolysaccharide (LPS), flagellin, peptidoglycan or DNA may bind directly to the TLR but in addition, co-receptors are needed to enhance the TLR response to these conserved ligands [1][2][3]. Myeloid cells use CD14 and MD-2 as co-receptors for LPS in TLR4 signalling, and minute amounts of LPS may elicit a strong systemic inflammatory response [4,5]. However, the TLR response to pathogen attack at mucosal surfaces is controlled by different interactions. Epithelial cells must be protected from constant TLR activation by commensals and their PAMP, in order for mucosal integrity to be maintained. The epithelial cells thus lack co-receptors like CD14 [6][7][8][9][10][11], and in addition, commensals have been suggested to actively suppress epithelia responses through NF-jB [12,13]. Yet, mucosal pathogens evoke rapid TLR4-dependent responses at mucosal sites, suggesting that alternative ligands and receptors might be involved in mucosal TLR activation. Pathogens use adhesive surface ligands to break the inertia of the mucosal barrier [14][15][16]. The innate defence is activated as a direct result of these interactions and epithelial cells produce the first wave of me...

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“…IRF-3 and expression of IFN-g [17,18]. Moreover, production of certain inflammatory cytokines in response to LPS and poly(I:C) but not upon stimulation of TLR2, TLR7, and TLR9 was severely impaired in TRIF-defective macrophages and fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, the adaptor protein TRAM interacts with TRIF and is required for MyD88-indpendent signaling of TLR4 but not TLR3 [19,20]. Combined null mutations for both TRIF and MyD88 completely abrogated signal transduction by TLR4, suggesting that only these two signaling pathways emanate from TLR4 [17,18].…”

Section: Introductionmentioning

confidence: 99%

Identification of a TLR4‐ and TRIF‐dependent activation program of dendritic cells

et al. 2004

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Dendritic cell activation by Toll-like receptors (TLR) is crucial for the generation of protective immune responses. In addition to the common myeloid differentiation factor 88 (MyD88)-dependent signaling pathway, TLR4 engages the adaptor protein Toll/IL-1 receptor (TIR)-domain-containing adaptor inducing IFN-g (TRIF), leading to interferon regulatory factor 3 (IRF-3) activation and type I interferon production. Using microarray expression profiling we now identify TRIF as a major regulator of the TLR4-triggered activation program of dendritic cells. We show that the expression of 47% of the genes that are responsive to TLR4 stimulation in wild-type dendritic cells is significantly altered in cells carrying a loss-of-function mutation of TRIF. Specifically, expression of IL-12, IL-18, and IL-23 was impaired in the absence of functional TRIF, suggesting that TLR4-promoted Th1 responses are TRIFdependent. Furthermore, we provide evidence that TRIF regulates TLR4-mediated gene expression both by type I IFN-dependent and -independent mechanisms. Whereas dendritic cell production of CXCL10 and CCL12 was dependent on both TRIF and the type I interferon receptor, expression of IL-6 required TRIF but not type I interferon activity. Functional TRIF was also required for the normal induction of numerous genes considered important for host defense against diverse pathogens. Together, these data therefore identify TRIF as a crucial regulator of TLR4-dependent dendritic cell responses.

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Identification of Lps2 as a key transducer of MyD88-independent TIR signalling

Cited by 1,121 publications

References 31 publications

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

Identification of a TLR4‐ and TRIF‐dependent activation program of dendritic cells

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