TLR1- and TLR6-independent Recognition of Bacterial Lipopeptides

Buwitt-Beckmann, Ute; Heine, Holger; Wiesmüller, Karl‐Heinz; Jung, Günther; Brock, Roland; Akira, Shizuo; Ulmer, Artur J.

doi:10.1074/jbc.m512525200

Cited by 227 publications

(201 citation statements)

References 39 publications

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“…Thus, the number of acyl chain of lipoproteins is finely differentiated by TLR1-TLR2 and TLR2-TLR6. In addition to the number of acyl chains, other characteristics, such as length and ester bond of acyl chains, are critical for the biological activity of TLR2-dependent signalling [19,20]. These results suggest that the fatty acid composition plays a central role in ligand recognition and receptor activation for TLR2.…”

Section: Introductionmentioning

confidence: 72%

Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse

Kuo¹,

Tsai

Jiang³

et al. 2010

Diabetologia

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Aims/hypothesis Substantial evidence suggests a link between elevated inflammation and development of insulin resistance. Toll-like receptor 2 (TLR2) recognises a large number of lipid-containing molecules and transduces inflammatory signalling in a variety of cell types, including insulin-responsive cells. Considering the contribution of the fatty acid composition in TLR2-depedent signalling, we hypothesised that the inflammatory signals transduced by TLR2 contribute to insulin resistance.Methods Mice deficient in TLR2 were used to investigate the in vivo roles of TLR2 in initiating and maintaining inflammation-associated insulin resistance and energy homeostasis.Results We first recapitulated the observation with elevated expression of TLR2 and inflammatory cytokines in white adipose tissue and liver of ob/ob mice. Aged or high-fat-fed TLR2-deficient mice were protected from obesity and adipocyte hypertrophy compared with wild-type mice. Moreover, mice lacking TLR2 exhibited improved glucose tolerance and insulin sensitivity regardless of feeding them regular chow or a high-fat diet. This is accompanied by reductions in expression of inflammatory cytokines and activation of extracellular signal-regulated kinase (ERK) in a liver-specific manner. The attenuated hepatic inflammatory cytokine expression and related signalling are correlated with increased insulin action specifically in the liver in TLR2-deficient mice, reflected by increased insulinstimulated protein kinase B (Akt) phosphorylation and IRS1 tyrosine phosphorylation and increased insulinsuppressed hepatocyte glucose production. Conclusions/interpretation The absence of TLR2 attenuates local inflammatory cytokine expression and related signalling and increases insulin action specifically in the liver. Thus, our work has identified TLR2 as a key mediator of hepatic inflammation-related signalling and insulin resistance.

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Section: Introductionmentioning

confidence: 72%

Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse

Kuo¹,

Tsai

Jiang³

et al. 2010

Diabetologia

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“…77,85,87,89 Although diacyl lipopeptides have been reported to be agonists of heterodimers of TLR2/ TLR6, 86,90,91 and triacylated species were thought to signal via TLR2/TLR1, 77,87,89 the recognition of the lipopeptides by TLR2 has been recently shown to be relatively independent of TLR1 and TLR6, and are mediated predominantly via TLR2. 92,93 Structural basis for the interactions of PAM 2 CSK 4 with TLR2 and PAM 3 CSK 4 with TLR2/TLR1. The crystal structures of both PAM 2 CSK 4 and PAM 3 CSK 4 with TLR1-TLR2 heterodimers have recently been determined (Fig.…”

Section: Tlr4 Agonists-lipopolysaccharide Monophosphoryl Lipid a Andmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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“…In addition, several reports documented that some distinct properties of lipopeptides are recognized by TLR2 in a TLR1-and TLR6-independent manner in human (13,26). TLR2 appears to be sufficient to signal the presence of PGN of mycobacteria and Gram-positive bacteria in mammals (10,27,28).…”

mentioning

confidence: 99%

“…TLR2 appears to be sufficient to signal the presence of PGN of mycobacteria and Gram-positive bacteria in mammals (10,27,28). In addition, the response to PGN is not renounced in either TLR1-or TLR6-deficient mice (15,26). It is still unclear if in mammals TLRs other than TLR1 and TLR6 pair with TLR2 to recognize PGN or TLR2 alone is sufficient to detect it.…”

mentioning

confidence: 99%

Combinational recognition of bacterial lipoproteins and peptidoglycan by chicken Toll-like receptor 2 subfamily

Higuchi

Matsuo

Shingai

et al. 2008

Developmental & Comparative Immunology

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2 SummaryHuman TLR2 subfamily recognizes bacterial lipoproteins (BLP) and peptidoglycan (PGN). According to the genome information, chicken has structural orthologs of TLRs 1 and 2, in addition to TLRs3, 4, 5 and 7. Chicken has two additional TLRs, TLR15 and TLR21, which orthologs human lacks. The chicken (ch)TLR1 and 2 genes are individually duplicated to encode for two different proteins, chTLRs, chTLR1-1, 1-2, 2-1 and 2-2, of the TLR2 subfamily. Here we investigated the functional profile of these TLR2 subfamily proteins of chicken. By NF-κB reporter assay using HEK293 cells, we found that chTLR2-1 and chTLR1-2 cooperatively signal the presence of PGN. A combination of chTLR2-1 and chTLR1-2 also most efficiently recognized diacylated BLP, Malp-2, while the combination of chTLR2-1 and chTLR1-1 failed to recognize Malp-2. All combinations, however, recognized triacylated BLP, Pam3. Consistent with these results, human TLR2-stimulating mycobacteria preparations, BCG-cell wall and cell lysate of Mycobacterium avium, induced activation of NF-κB in cells expressing chTLR2-1 and 1-2 and to lesser extents, cells with chTLR2-2 and either of chTLR1. Strikingly, expression of either of these alone did not activate the reporter for NF-κB. These chTLRs are likely to have the combination functional feature as in the human TLR2 subfamily. Confocal and immunoprecipitation analyses of human cell transfectants showed that they cluster on the cell surface by a physical molecular association, causing all of them to merge and coprecipitate. These results suggest that chTLR2 subfamily members discriminate between their ligands by combinational events.

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TLR1- and TLR6-independent Recognition of Bacterial Lipopeptides

Cited by 227 publications

References 39 publications

Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse

Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse

Potential adjuvantic properties of innate immune stimuli

Combinational recognition of bacterial lipoproteins and peptidoglycan by chicken Toll-like receptor 2 subfamily

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