CD14 Controls the LPS-Induced Endocytosis of Toll-like Receptor 4

Zanoni, Ivan; Ostuni, Renato; Marek, Lorri R.; Barresi, Simona; Barbalat, Roman; Barton, Gregory M.; Granucci, Francesca; Kagan, Jonathan C.

doi:10.1016/j.cell.2011.09.051

Cited by 812 publications

(991 citation statements)

References 43 publications

Supporting

Mentioning

899

Contrasting

Unclassified

Order By: Relevance

“…To determine if UT12-induced TLR4 internalization and IRF3 activation involves the same signaling molecules reported for LPS (12), we tested the effect of the Syk and PLC-γ2 inhibitors, piceatannol and U73122, respectively. Both inhibitors blocked LPS-and UT12-induced TLR4 internalization and IRF3 activation similarly (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Rab11a, ARF6, and p120-catenin have been implicated in Escherichia coli/LPS-induced TLR4 endocytosis and IRF3 activation (9-11). Zanoni et al showed that CD14 plays critical roles in translocation of TLR4 into endosomes and in activation of IRF3 that are dependent upon the enzymatic activities of PLCγ2 and Syk (12). However, CD14-independent TLR4 endocytosis and TRIF signaling have not been reported.…”

mentioning

confidence: 99%

See 1 more Smart Citation

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

Rajesh

Perkins

Ireland

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

123

104

View full text Add to dashboard Cite

Dimerization of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) heterodimers is critical for both MyD88-and TIRdomain-containing adapter-inducing IFN-β (TRIF)-mediated signaling pathways. Recently, Zanoni et al. [(2011) Cell 147(4):868-880] reported that cluster of differentiation 14 (CD14) is required for LPS-/Escherichia coli-induced TLR4 internalization into endosomes and activation of TRIF-mediated signaling in macrophages. We confirmed their findings with LPS but report here that CD14 is not required for receptor endocytosis and downstream signaling mediated by TLR4/MD2 agonistic antibody (UT12) and synthetic small-molecule TLR4 ligands (1Z105) in murine macrophages. CD14 deficiency completely ablated the LPS-induced TBK1/IRF3 signaling axis that mediates production of IFN-β in murine macrophages without affecting MyD88-mediated signaling, including NF-κB, MAPK activation, and TNF-α and IL-6 production. However, neither the MyD88-nor TRIF-signaling pathways and their associated cytokine profiles were altered in the absence of CD14 in UT12-or 1Z105-treated murine macrophages. Eritoran (E5564), a lipid A antagonist that binds the MD2 "pocket," completely blocked LPS-and 1Z105-driven, but not UT12-induced, TLR4 dimerization and endocytosis. Furthermore, TLR4 endocytosis is induced in macrophages tolerized by exposure to either LPS or UT12 and is independent of CD14. These data indicate that TLR4 receptor endocytosis and the TRIF-signaling pathway are dissociable and that TLR4 internalization in macrophages can be induced by UT12, 1Z105, and during endotoxin tolerance in the absence of CD14. T oll-like receptor 4 (TLR4) signaling plays a crucial role in host defense against Gram-negative bacteria by recognizing the outer membrane component, lipopolysaccharide (LPS) (1-3). TLR4 signaling is initiated by transfer of an LPS monomer from LPS binding protein (LBP) to cluster of differentiation 14 (CD14) (GPI-linked or soluble). In turn, CD14 transfers monomeric LPS to myeloid differentiation factor 2 (MD-2), a protein that associates noncovalently with TLR4 (4). Appropriate ligand binding to MD2 results in dimerization of two TLR4/MD2 complexes (4). TLR4 is unique in that it is the only TLR that activates both myeloid differentiation primary response 88 (MyD88) and TIR-domain-containing adapter-inducing IFN-β (TRIF)-dependent signaling pathways (5, 6). MyD88-mediated, TLR4 signaling occurs mainly at plasma membranes and involves IL-1R-associated kinases phosphorylation, association of TNF-receptor-associated factor 6, and downstream signaling that results in NF-κB activation and induction of proinflammatory mediators such as TNF-α and IL-6 (7). In contrast, TRIF-mediated signaling in response to LPS occurs at the endosomal membrane after internalization of the TLR4 that, in turn, activates IFN regulatory factor 3 (IRF3), resulting in production of IFN-β, IP-10, and other IRF-3-dependent genes, as well as delayed NF-κB activation (8). Recent studies have shown that the endocytosis of TLR4 is tight...

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

Rajesh

Perkins

Ireland

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

123

104

View full text Add to dashboard Cite

show abstract

“…Zanoni et al 30, 47, 77. have shown that LPS‐primed BMDC are programmed for apoptosis, unlike LPS‐primed macrophages which, although refractory to a second challenge of LPS, survive in culture for prolonged periods.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

et al. 2016

View full text Add to dashboard Cite

SummaryExposure of bone‐marrow‐derived dendritic cells (BMDC) to high‐dose ultrapure lipopolysaccharide for 24 hr (LPS‐primed BMDC) enhances their potency in preventing inter‐photoreceptor retinoid binding protein: complete Freund's adjuvant‐induced experimental autoimmune uveoretinitis (EAU). LPS‐primed BMDC are refractory to further exposure to LPS (= endotoxin tolerance), evidenced here by decreased phosphorylation of TANK‐binding kinase 1, interferon regulatory factor 3 (IRF3), c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase as well as impaired nuclear translocation of nuclear factor κB (NF‐κB) and IRF3, resulting in reduced tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), IL‐12 and interferon‐β secretion. LPS‐primed BMDC also show reduced surface expression of Toll‐like receptor‐4 and up‐regulation of CD14, followed by increased apoptosis, mediated via nuclear factor of activated T cells (NFATc)‐2 signalling. LPS‐primed BMDC are not only homotolerant to LPS but are heterotolerant to alternative pathogen‐associated molecular pattern ligands, such as mycobacterial protein extract (Mycobacterium tuberculosis). Specifically, while M. tuberculosis protein extract induces secretion of IL‐1β, TNF‐α and IL‐6 in unprimed BMDC, LPS‐primed BMDC fail to secrete these cytokines in response to M. tuberculosis. We propose that LPS priming of BMDC, by exposure to high doses of LPS for 24 hr, stabilizes their tolerogenicity rather than promoting immunogenicity, and does so by multiple mechanisms, namely (i) generation of tolerogenic apoptotic BMDC through CD14:NFATc signalling; (ii) reduction of NF‐κB and IRF3 signalling and downstream pro‐inflammatory cytokine production; and (iii) blockade of inflammasome activation.

show abstract

“…Considering these points, we assumed that FOXO is involved in an endosomal pathway that requires uptake and degradation of the pathogen. TLR3 is one of the pattern recognition receptors localized in the endosomal compartment (12,38) and can easily be targeted, unlike TLR4, which is additionally expressed on the cell membrane, thereby triggering distinct signaling mechanisms that are difficult to discriminate (39). Therefore, we decided to focus on TLR3 signaling.…”

Section: Discussionmentioning

confidence: 99%

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

Seiler

Hellberg

Lepper

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Bacterial pathogens are a leading cause of lung infections and contribute to acute exacerbations in patients with chronic respiratory diseases. The innate immune system of the respiratory tract controls and prevents colonization of the lung with bacterial pathogens. Forkhead box transcription factor family O (FOXO) transcription factors are key regulators of cellular metabolism, proliferation, and stress resistance. In this study, our aim was to investigate the role of FOXO transcription factors in innate immune functions of respiratory epithelial cells. We show that bacterial pathogens potently activate FOXO transcription factors in cultured human respiratory epithelial cells in vitro. Infection of mice with bacterial pathogens resulted in the activation of FOXO transcription factors in alveolar and bronchial epithelial cells in vivo. Active FOXO was also detectable in human bronchial tissue obtained from subjects with different infection-related lung diseases. Small interfering RNA–mediated knockdown of FOXO in bronchial epithelial cells resulted in reduced expression of factors of the innate immune system such as antimicrobial peptides and proinflammatory cytokines, both under basal conditions and upon infection. FOXO deficiency further affected internalization of Haemophilus influenzae in bronchial epithelial cells. Finally, we show that TLR3 activates innate immune responses in a FOXO-dependent manner. In conclusion, FOXO transcription factors are involved in the cellular responses to bacterial stimuli and act as central regulators of innate immune functions in respiratory epithelial cells.

show abstract

CD14 Controls the LPS-Induced Endocytosis of Toll-like Receptor 4

Cited by 812 publications

References 43 publications

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

FOXO Transcription Factors Regulate Innate Immune Mechanisms in Respiratory Epithelial Cells

Contact Info

Product

Resources

About