Cutting Edge: Lipopolysaccharide Induces Physical Proximity Between CD14 and Toll-Like Receptor 4 (TLR4) Prior to Nuclear Translocation of NF-κB

Jiang, Qingqi; Akashi, Shigeo; Miyake, Kensuke; Petty, Howard R.

doi:10.4049/jimmunol.165.7.3541

Cited by 297 publications

(220 citation statements)

References 29 publications

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“…Transfer of LPS to CD14 via LBP and a physical association of CD14 with TLR4/MD-2, have been identified as necessary events in the activation of cells such as macrophages by LPS [15,27,28]. The expression of CD14 on MC is still a matter of dispute [29][30][31][32][33][34].…”

Section: Activation Of MC By R-form Lps Is Independent Of Lbp and Cd14mentioning

confidence: 99%

R‐form LPS, the master key to the activation ofTLR4/MD‐2‐positive cells

et al. 2006

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Lipopolysaccharide (endotoxin, LPS) is a major recognition marker for the detection of gram-negative bacteria by the host and a powerful initiator of the inflammatory response to infection. Using S-and R-form LPS from wild-type and R-mutants of Salmonella and E. coli, we show that R-form LPS readily activates mouse cells expressing the signaling receptor Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), while the S-form requires further the help of the LPS-binding proteins CD14 and LBP, which limits its activating capacity. Therefore, the R-form LPS under physiological conditions recruits a larger spectrum of cells in endotoxic reactions than S-form LPS. We also show that soluble CD14 at high concentrations enables CD14-negative cells to respond to S-form LPS. The presented in vitro data are corroborated by an in vivo study measuring TNF-a levels in response to injection of R-and S-form LPS in mice. Since the R-form LPS constitutes ubiquitously part of the total LPS present in all wild-type bacteria its contribution to the innate immune response and pathophysiology of infection is much higher than anticipated during the last half century.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35593_pdf IntroductionThe interaction of highly conserved microbial constituents with the innate immune system forms the basis of recognition of and reaction against intruding pathogens in mammals. One such constituent is lipopolysaccharide (endotoxin, LPS), a major recognition marker common to gram-negative bacteria [1][2][3], a large group comprising important human pathogens as well as commensals. Thus, the interaction of LPS with cells of the innate immune system leads to the formation and release of endogenous mediators initiating inflammatory and immune responses essential for an antibacterial defense [3,4]. This primarily protective mechanism may become overshadowed by an acute pathophysiological response with the typical clinical symptoms of septic shock that frequently follows the release of inflammatory mediators, such as tumor necrosis factor (TNF)-a during infection [5][6][7].Innate immunity * Both authors contributed equally to this work. [10]. Binding of allergen to its specific IgE on the surface of MC results in an immediate release of preformed pro-inflammatory mediators (e.g., histamine, TNF-a and proteases) from cytoplasmic granules (degranulation) [11] and a later release of de novo synthesized arachidonic acid metabolites and various cytokines like interleukin 6 (IL-6), TNF-a, and chemokines [10,11]. Unlike allergens, LPS induces no degranulation of MC, but like allergens, it stimulates the de novo synthesis and release of cytokines in these cells [9].Activation of cells by LPS is mediated by the Toll-like receptor 4 (TLR4), a member of the highly conserved protein family of TLR, which are specialized in the recognition of microbial components. In mice, defects in TLR4 result in LPS unresponsiveness [12]. For functional interaction with LP...

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Section: Activation Of MC By R-form Lps Is Independent Of Lbp and Cd14mentioning

confidence: 99%

R‐form LPS, the master key to the activation ofTLR4/MD‐2‐positive cells

et al. 2006

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“…Because CD14 is a GPI-anchored protein devoid of a transmembrane domain, by itself, it presumably cannot transmit the activating signal into the cell. Indeed, in vitro work has demonstrated that Toll-like receptor 4 (TLR4) 3 activates the immune system by functioning as a transmembrane coreceptor to CD14 (16,17). Both TLR4-deficient (TLR4 d ) mice and mice with a single point mutation at aa 712 (proline to histidine) in the TLR4 gene (C3H/HeJ) are resistant to the immunostimulatory and pathophysiological effects of LPS (18,19).…”

mentioning

confidence: 99%

Lipopolysaccharide-Induced Leukocyte-Endothelial Cell Interactions: A Role for CD14 Versus Toll-Like Receptor 4 Within Microvessels

Andonegui

Goyert

Kubes

2002

The Journal of Immunology

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The objective of this study was to systematically assess leukocyte-endothelial cell interactions in vivo in response to LPS in CD14-deficient (CD14−/−) and Toll-like receptor 4-deficient (TLR4d; C3H/HeJ) mice. Local injection of LPS (0.05 μg/kg) into muscle at a concentration that did not cause systemic effects produced a significant reduction in the speed with which leukocytes roll and a substantial increase in leukocyte adhesion and emigration 4 h postinjection. There was no response to LPS in the muscle microvasculature of CD14−/− mice or TLR4d animals. Systemic LPS induced leukopenia and significant sequestration of neutrophils in lungs in wild-type mice but not in CD14−/− or TLR4d mice. P-selectin expression was examined in numerous mouse organs using a dual radiolabeling mAb technique. The results revealed a 20- to 50-fold increase in P-selectin expression in response to LPS in all wild-type tissues examined but no response in any TLR4d tissues. Surprisingly, there was consistently a partial, significant increase in P-selectin expression in numerous microvasculatures including skin and pancreas, but no increase in P-selectin was detected in lung, muscle, and other organs in CD14−/− mice in response to LPS. Next, the skin and muscle microcirculation were visualized using intravital microscopy after systemic LPS treatment, and the results confirmed a CD14-independent mechanism of leukocyte sequestration in skin but not muscle. In summary, our results suggest that the LPS-induced leukocyte sequestration to some tissues is entirely dependent on both CD14 and TLR4 but there are CD14-independent, TLR4-dependent endothelial cell responses in some microvascular beds.

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“…In addition, it was demonstrated that the physical approximation between CD14 and TLR4 precedes the nuclear translocation of NF-κB and that TLR4 requires CD14 to participate in the process of signaling induced by LPS 41 .…”

Section: Role Of Toll-like Receptor (Tlr4) In the Receptor Complex Ofmentioning

confidence: 99%

“…According to Jiang et al (2000) 41 , there is a physical association of CD14 and TLR4 dependent on LPS. However, the authors did not discern if the binding of LPS triggers a lateral association of these receptors in the plasma membrane or if it occurs during the release of the pre-associated CD14 and TLR4 by an intracellular tool near the membrane.…”

Section: Role Of Toll-like Receptor (Tlr4) In the Receptor Complex Ofmentioning

confidence: 99%

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Role of endotoxin in the etiology of periapical lesions: molecular mechanisms involved in endotoxin's recognition and cell activation

Lucisano

Filho

Silva

et al. 2014

RGO, Rev. Gaúch. Odontol.

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Periapical lesions are diseases resulting from contamination and necrosis of dental pulp and the progression of this infection toward the periapical tissues. Technological advances in microbiological culture and identification have shown that anaerobic microorganisms, especially Gram-negative, are RESUMOAs lesões periapicais são patologias resultantes da contaminação e necrose da polpa dental e progressão da infecção em direção aos tecidos periapicais. Os avanços tecnológicos na cultura e identificação microbiana demonstraram que, em canais radiculares de dentes portadores de necrose pulpar e lesão periapical crônica, predominam os microrganismos anaeróbios, particularmente os Gram-negativos. As bactérias Gram-negativas, além de possuírem diferentes fatores de virulência e gerarem produtos e subprodutos tóxicos aos tecidos apicais e periapicais, contêm a endotoxina em sua parede celular. Esse conhecimento é importante, uma vez que a endotoxina é liberada durante a multiplicação ou morte bacteriana, exercendo uma série de efeitos biológicos relevantes, que conduzem a uma reação inflamatória e à reabsorção dos tecidos mineralizados. Sendo assim, o objetivo deste trabalho foi efetuar uma revisão da literatura relativa ao papel da endotoxina bacteriana na etiologia das lesões periapicais, seu mecanismo de ação, bem como elucidar mecanismos moleculares envolvidos no seu reconhecimento pelo sistema imunológico e na ativação celular. Role of endotoxin in the etiology of periapical lesions: molecular mechanisms involved in endotoxin's recognition and cell activationPapel da endotoxina na etiologia da lesão periapical: mecanismos moleculares envolvidos no seu reconhecimento e na ativação celular

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Cutting Edge: Lipopolysaccharide Induces Physical Proximity Between CD14 and Toll-Like Receptor 4 (TLR4) Prior to Nuclear Translocation of NF-κB

Cited by 297 publications

References 29 publications

R‐form LPS, the master key to the activation ofTLR4/MD‐2‐positive cells

R‐form LPS, the master key to the activation ofTLR4/MD‐2‐positive cells

Lipopolysaccharide-Induced Leukocyte-Endothelial Cell Interactions: A Role for CD14 Versus Toll-Like Receptor 4 Within Microvessels

Role of endotoxin in the etiology of periapical lesions: molecular mechanisms involved in endotoxin's recognition and cell activation

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