Unresponsiveness of MyD88-Deficient Mice to Endotoxin

Kawai, Taro; Adachi, Osamu; Ogawa, Tomohiko; Takeda, Kiyoshi; Akira, Shizuo

doi:10.1016/s1074-7613(00)80086-2

Cited by 1,889 publications

(1,559 citation statements)

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“…As a consequence, systemic LPS responses are severely decreased in Myd88 -/-, Irak -/-and Tirap -/-mice [29,31,32]. In view of the CD14 and LPS independence of the epithelial response to P fimbriated E. coli, we speculated that TLR4 signalling might utilise adaptor proteins other than MyD88 and TIRAP.…”

Section: Resultsmentioning

confidence: 97%

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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Section: Resultsmentioning

confidence: 97%

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

et al. 2006

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“…Even the LPS recognition complex and signal transduction pathway involves many candidate genes, in which various polymorphisms may alter phenotype. These include candidate polymorphisms in genes for bactericidal/ permeability increasing protein, LBP, 6,33 CD14, 34-36 MD-2, 37 Myeloid Differentiation Factor 88 (MyD88), 38,39 and IL-1 receptor-associated kinase (IRAK). 40,41 As other have stated, the genetic determinants responsible for the host response to injury or infection are largely polygenic or weakly penetrant.…”

Section: Discussionmentioning

confidence: 99%

The TLR4 +896 polymorphism is not associated with lipopolysaccharide hypo-responsiveness in leukocytes

et al. 2004

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Toll-like receptor 4 (TLR-4) is required for detection of Gram negative bacterial infections by binding lipopolysaccharide (LPS) and for the initiation of inflammatory signaling. Recent studies have demonstrated that a nonsynonymous single-nucleotide polymorphism (Asp299Gly, A þ 896G) is associated with decreased endotoxin responsiveness and poor outcomes from sepsis. We show that human carriers of this polymorphism show no deficit in LPS induced peripheral blood mononuclear cell (PBMC) mitogen-activated protein kinase (MAPK) activity, no reduction in sensitivity to endotoxin, and variable differences in whole-blood inflammatory cytokine production. These results indicate that this mutation is not a primary determinant of human endotoxin sensitivity.

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“…TRIF-dependent signaling to NF-kB Somewhat unexpectedly, when exposed to LPS, MyD88 À/À cells display partial NF-kB activation, albeit with slower kinetics than in wild-type cells (Kawai et al, 1999). When cells are stimulated through TLR3 and TLR4, TRIF (TICAM-1), a TIR-domain containing adapter, mediates activation of NF-kB in the absence of MyD88 (Oshiumi et al, 2003).…”

Section: Toll-like Receptorsmentioning

confidence: 99%