CD14 is a coreceptor of Toll-like receptors 7 and 9

Baumann, Christoph; Aspalter, Irene M.; Sharif, Omar; Pichlmair, Andreas; Blüml, Stephan; Grebien, Florian; Brückner, Manuela; Pasierbek, Paweł; Aumayr, Karin; Planyavsky, Melanie; Bennett, Keiryn L.; Colinge, Jacques; Knapp, Sylvia; Superti‐Furga, Giulio

doi:10.1084/jem.20101111

Cited by 200 publications

(206 citation statements)

References 55 publications

(83 reference statements)

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“…Because TLR3 is located in endosomes and its ligand, polyinosinic:polycytidylic acid (pI:C), strongly induces IFN-β, we assessed the involvement of CD14 in TLR3 signaling. Several reports have provided evidence for the requirement of CD14 in TLR3-mediated signaling (22,23). Lee et al claimed that CD14 physically interacts with pI:C and mediates TLR3 activation (23).…”

Section: Resultsmentioning

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.

125

104

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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...

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Section: Resultsmentioning

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.

125

104

View full text Add to dashboard Cite

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“…Adaptor molecule CD14 has been shown to aid several receptor complexes, including TLR4-MD2, TLR7, and TLR9 in recognition of lipid A, single-stranded RNA, and double-stranded bacterial CpG DNA, respectively (58,61,79). Interestingly, blocking CD14 by neutralizing antibodies or genetic deficiency for this molecule on microglia results in reduced levels of immune activation by ␤-amyloid (76).…”

Section: Discussionmentioning

confidence: 99%

CD14 Protein Acts as an Adaptor Molecule for the Immune Recognition of Salmonella Curli Fibers

Rapsinski

Newman

Oppong

et al. 2013

Journal of Biological Chemistry

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Background: Curli fibers are recognized by the TLR2/TLR1 complex. Results: CD14 binds curli fibers and enhances TLR2/TLR1-dependent NF-B activation as well as cytokine and nitrite production. Conclusion: CD14 is an adaptor protein for the TLR2/TLR1 complex binding the fibrillar structure of curli fibers. Significance: Understanding the immune receptor complexes that recognize amyloids will have implications for amyloidassociated diseases.

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“…Spitzer et al [76] have demonstrated that TLR1 interacts and modulates the signaling of TLR4 and also that CD14 is required for both TLR4-and TLR2-dependent signaling. Finally, CD14 also interacts with endosomal TLR8 [77][78][79]. So many candidate receptors of aPLA seem to be involved in endocytosis process suggesting a commonality in aPLA-mediated cell activation ( Fig.…”

Section: Internalization and Apla Receptorsmentioning

confidence: 93%

Receptors involved in cell activation by antiphospholipid antibodies

Brandt

Kruithof

Moerloose

2013

Thrombosis Research

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The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2+ -binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS

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CD14 is a coreceptor of Toll-like receptors 7 and 9

Abstract: CD14 interacts with and is essential for the functions of endosomal TLR7 and TLR9 in mice.

Cited by 200 publications

References 55 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

CD14 Protein Acts as an Adaptor Molecule for the Immune Recognition of Salmonella Curli Fibers

Receptors involved in cell activation by antiphospholipid antibodies

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