TLR2 – promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity

Zähringer, Ulrich; Lindner, Buko; Inamura, Seiichi; Heine, Holger; Alexander, Christian

doi:10.1016/j.imbio.2008.02.005

Cited by 350 publications

(360 citation statements)

References 134 publications

(145 reference statements)

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“…Snap-frozen brains were homogenized by sonication in ice-cold homogenization buffer containing PMSF (P7626 Sigma), dimethyl sulfoxide (D2650, Sigma), and cell lysis buffer factor 1 and factor 2 (Bio-Plex Cell Lysis Kit; Life Science Research, Hercules, California 17], and interferon γ [IFN-γ]) was measured with the Bio-Plex Multiplex Cytokine Assay (Bio-Rad). Data were acquired on a Luminex 200 system (Bio-Rad).…”

Section: Multiplex Cytokine and Chemokine Assaymentioning

confidence: 99%

“…Although S. epidermidis infection results in relatively low mortality, it is associated with an increased risk of common adverse outcomes, prolonged hospital stays, and increased costs [15,16]. Staphylococcus epidermidis, via expression of soluble factors, including lipopeptides, activates host responses in part via Toll-like receptor 2 (TLR2) [17], which mediates recognition and clearance of S. epidermidis bacteremia in adult mice in vivo [18]. Moreover, repeated systemic (intraperitoneal) administration of the bacterial lipopeptide TLR2 agonist Pam 3 CSK 4 adversely influences brain development in newborn mice [19], raising the possibility that bacteremia due to pathogens that activate TLR2, such as S. epidermidis, may trigger neonatal brain injury even in the absence of entry of bacteria into the central nervous system (CNS).…”

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confidence: 99%

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Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Bi¹,

Qiao²,

Bergelson³

et al. 2015

J Infect Dis.

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Background. Staphylococcus epidermidis causes late-onset sepsis in preterm infants. Staphylococcus epidermidis activates host responses in part via Toll-like receptor 2 (TLR2). Epidemiologic studies link bacteremia and neonatal brain injury, but direct evidence is lacking.Methods. Wild-type and TLR2-deficient (TLR2−/−) mice were injected intravenously with S. epidermidis at postnatal day 1 prior to measuring plasma and brain cytokine and chemokine levels, bacterial clearance, brain caspase-3 activation, white/gray matter volume, and innate transcriptome.Results. Staphylococcus epidermidis bacteremia spontaneously resolved over 24 hours without detectable bacteria in the cerebrospinal fluid (CSF). TLR2−/− mice demonstrated delayed S. epidermidis clearance from blood, spleen, and liver. Staphylococcus epidermidis increased the white blood cell count in the CSF, increased interleukin 6, interleukin 12p40, CCL2, and CXCL1 concentrations in plasma; increased the CCL2 concentration in the brain; and caused rapid (within 6 hours) TLR2-dependent brain activation of caspase-3 and TLR2-independent white matter injury.Conclusions. Staphylococcus epidermidis bacteremia, in the absence of bacterial entry into the CSF, impairs neonatal brain development. Staphylococcus epidermidis bacteremia induced both TLR2-dependent and -independent brain injury, with the latter occurring in the absence of TLR2, a condition associated with an increased bacterial burden. Our study indicates that the consequences of transient bacteremia in early life may be more severe than commonly appreciated, and our findings may inform novel approaches to reduce bacteremia-associated brain injury.

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Section: Multiplex Cytokine and Chemokine Assaymentioning

confidence: 99%

mentioning

confidence: 99%

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Bi¹,

Qiao²,

Bergelson³

et al. 2015

J Infect Dis.

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“…TLR2 detects a broader range of bacterial pathogen-associated molecular patterns than other TLRs [24], but of the various TLR agonists that are currently under investigation as adjuvants in anticancer therapies, none is TLR2-specific [2,12]. In contrast to all other TLRs, TLR2 forms heterodimers: diacylated lipoproteins are recognized by a heterodimer of TLR2 with TLR6 (TLR2/6), while recognition of triacylated lipoproteins requires heterodimerization of TLR2 with TLR1 (TLR2/1) [25,26].…”

Section: Introductionmentioning

confidence: 99%

“…Consistent with this hypothesis, we have previously reported the ability of non-methylated CpG oligonucleotides, the ligand for TLR9, to exert direct effects on pediatric B-cell precursor (BCP) ALL cells and to generate antileukemia immune responses [22,23]. Given these encouraging findings, the activity of other TLRs in the setting of ALL is of considerable interest.TLR2 detects a broader range of bacterial pathogen-associated molecular patterns than other TLRs [24], but of the various TLR agonists that are currently under investigation as adjuvants in anticancer therapies, none is TLR2-specific [2,12]. In contrast to all other TLRs, TLR2 forms heterodimers: diacylated lipoproteins are recognized by a heterodimer of TLR2 with TLR6 (TLR2/6), while recognition of triacylated lipoproteins requires heterodimerization of TLR2 with TLR1 (TLR2/1) [25,26].…”

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confidence: 99%

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

et al. 2015

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Reports of spontaneous acute lymphoblastic leukemia (ALL) remissions following severe bacterial infections suggest that bacterial components may trigger elimination of ALL. To date, TLR2, which recognizes a broad range of bacterial pathogens through TLR1 or TLR6 heterodimerization, has not been fully evaluated for direct effects on ALL. Studies investigating TLR2 signaling in other tumor cell types utilizing single ligands have yielded contradictory results, and comparative, heterodimer-specific analyses of TLR2 stimulation are lacking. In this study, we report that two well-characterized heterodimer-specific TLR2 ligands, Pam 3 CSK 4 (TLR2/1), and Pam 2 CSK 4 (TLR2/6), induce ALL cell lines and primary ALL samples to upregulate CD40 expression. However, only Pam 3 CSK 4 triggers Caspase-8-mediated apoptosis and sensitizes cells to vincristine-mediated cytotoxicity. Consistent with this result, stimulation of ALL cells through TLR2/1 or TLR2/6 activates Mal, p38 and the NF-κB and PI3K signaling pathways with divergent kinetics that may underlie their distinct downstream effects. Our results reveal a novel branching in downstream responses to heterodimer-specific TLR2 stimulation in ALL cells and emphasize the need for comparative studies to determine differential biological effects observed in specific tumor cells. Based on our results, TLR2/1 ligand Pam 3 CSK 4 possesses potential for generating anti-ALL activity through its direct effects on leukemic blasts.Keywords: CD40 r Caspase-8-mediated apoptotic cell death r Heterodimer-specific TLR2 stimulation r Pediatric acute lymphoblastic leukemia r Signaling kinetics Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIt is now widely accepted that tumor remissions induced by the proinflammatory activity of Coley's toxin, which contains various bacterial components, is mediated by the engagement of TollCorrespondence: Dr. Kirk R. Schultz e-mail: kschultz@mail.ubc.ca like receptors (TLRs) on immune cells [1][2][3][4][5]. TLRs are a family of germline-encoded pattern recognition receptors that induce innate and adaptive immune responses after binding pathogenand damage-associated molecular patterns [6][7][8][9][10]. In recent years, many studies have demonstrated that purified TLR ligands exert * These authors contributed equally to this work as senior authors.www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1980-1990 Immunomodulation 1981 potent anti-cancer effects against various types of established tumors in both mice and humans [2,5]. However, while some TLR ligands are currently in clinical trials [11,12], their promising preclinical efficacy as anti-cancer agents has not been consistently observed in the clinic [12]. A greater understanding of the cellular and molecular processes that mediate the beneficial and detrimental outcomes of TLR signaling is needed in order to optimize the translation of this approach. Spontaneous remissions of acute lymphoblastic leukemia (ALL) associated with se...

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“…TLR2 can trigger the expression of proinflammatory cytokines upon the activation by binding to lipopeptides from bacteria. [9][10][11] In the current study, we investigated the activation pattern of TLR2 in septic AKI using lipopolysaccharide (LPS)-induced septic AKI mice as a model. The results of the study could identify cell subsets with TLR2 overactivation in septic AKI, consequently providing targets for improved septic AKI treatment development.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of toll-like receptor 2 in glomerular endothelial cells and podocytes in septic acute kidney injury mouse model

et al. 2015

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Acute kidney injury (AKI) is one of the most common complications in patients with severe sepsis. The development of septic AKI increases patients' mobility and even mortality. Toll-like receptor 2 (TLR2), as a membrane surface receptor for bacterial, fungal, viral and certain endogenous substances, has been described to contribute to the development of septic AKI; however, the renal cell types associating TLR2 overactivation in septic AKI has not been described. In the current study, we investigated the TLR2 activation patterns in the kidney of lipopolysaccharide-induced septic AKI mice. Our results demonstrated that mRNA level of TLR2 significantly increased in the kidney of lipopolysaccharide-treated mice. Immunohistochemistry revealed the overactivation of TLR2 in the glomeruli. Double immunofluorescence analysis shows the precise distribution of TLR2 by showing the colocalization of TLR2 in glomeruli with synaptopodin, a podocyte marker, and Tie2, an endothelial marker. In addition, proapoptotic molecules Bax and Caspase-3 were increased in the glomeruli of lipopolysaccharide-treated mice. Together, the current study indicates that TLR2 is overactivated in the glomerular endothelial cells and podocytes in septic AKI mice, while the abundance of Bax and Caspase-3 were increased in the glomeruli of these mice, it may supply a clue that TLR2 induced these cell apoptosis in AKI. This finding provides an alternative mechanism to understand AKI development and potential targets for treatment.

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TLR2 – promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity

Cited by 350 publications

References 134 publications

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

Overexpression of toll-like receptor 2 in glomerular endothelial cells and podocytes in septic acute kidney injury mouse model

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