Host Defense Mechanisms Triggered by Microbial Lipoproteins Through Toll-Like Receptors

Brightbill, Hans; Libraty, Daniel H.; Krutzik, Stephan R.; Yang, Ruey‐Bing; Belisle, John T.; Bleharski, Joshua R.; Maitland, Michael L.; Norgard, Michael V.; Plevy, Scott E.; Smale, Stephen T.; Brennan, Patrick J.; Bloom, Barry R.; Godowski, Paul J.; Modlin, Robert L.

doi:10.1126/science.285.5428.732

Cited by 1,490 publications

(1,119 citation statements)

References 40 publications

(29 reference statements)

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“…Our results confirmed that, similar to other bacterial lipoproteins tested in vitro [10,43,44], AaPAL-induced pro-inflammatory cytokine production by mouse macrophages is mediated by TLR2. The PAL of E. coli has also been shown to induce IL-6 and TNF-α production by mouse macrophages via TLR2 in vivo , as demonstrated by using a TLR2 knockout mouse model [22].…”

Section: Discussionsupporting

confidence: 89%

Peptidoglycan-associated lipoprotein ofAggregatibacter actinomycetemcomitansinduces apoptosis and production of proinflammatory cytokines via TLR2 in murine macrophages RAW 264.7in vitro

Ihalin

Eneslätt

Asikainen

2018

Journal of Oral Microbiology

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Peptidoglycan-associated lipoprotein (PAL) is a conserved pro-inflammatory outer membrane lipoprotein in Gram-negative bacteria. Compared to systemic pathogens, little is known about the virulence properties of PAL in Aggregatibacter actinomycetemcomitans (AaPAL). The aims of this study were to investigate the cytolethality of AaPAL and its ability to induce pro-inflammatory cytokine production in macrophages. Mouse macrophages were stimulated with AaPAL, and the production of IL-1β, IL-6, TNF-α, and MCP-1 was measured after 6, 24, and 48 h. To investigate which receptor AaPAL employs for its interaction with macrophages, anti-toll-like receptor (TLR)2 and anti-TLR4 antibodies were used to block respective TLRs on macrophages. Metabolic activity and apoptosis of the macrophages were investigated after stimulation with AaPAL. AaPAL induced the production of MCP-1, TNF-α, IL-6, and IL-1β from mouse macrophages in order of decreasing abundance. The pre-treatment of macrophages with an anti-TLR2 antibody significantly diminished cytokine production. Under AaPAL stimulation, the metabolic activity of macrophages decreased in a dose- and time-dependent manner. Furthermore, AaPAL induced apoptosis in 56% of macrophages after 48 h of incubation. Our data suggest that AaPAL can kill macrophages by apoptosis. The results also emphasize the role of AaPAL as a potent pro-inflammatory agent in A. actinomycetemcomitans-associated infections.

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Section: Discussionsupporting

confidence: 89%

Peptidoglycan-associated lipoprotein ofAggregatibacter actinomycetemcomitansinduces apoptosis and production of proinflammatory cytokines via TLR2 in murine macrophages RAW 264.7in vitro

Ihalin

Eneslätt

Asikainen

2018

Journal of Oral Microbiology

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“…43,70 While initial in vitro studies showed that cellular recognition of lipoproteins from a variety of microorganisms including Mycobacteria, Mycoplasma sp. and the spirochetes Treponema pallidum and B. burgdorferi is mediated by TLR2, 35,36,71 more recent work has revealed a functional interaction between TLR2 and TLR1 that enhances cellular signaling in response to B. burgdorferi lipoprotein OspA. 43 Macrophages from both TLR1-or TLR2-deficient mice incubated with OspA exhibit impaired cytokine and nitric oxide (NO) production compared to wild-type controls.…”

Section: Spirochetal Infectionmentioning

confidence: 99%

Toll-like receptors and their role in experimental models of microbial infection

2003

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Effective host defense against microbial infection depends upon prompt recognition of pathogens, activation of immediate containment measures, and ultimately the generation of a specific and definitive adaptive immune response. The innate immune system of the host is responsible for providing constant surveillance against infection; when confronted by pathogens it deploys a series of rapidly acting antimicrobial effectors while simultaneously instructing the adaptive immune system as to the nature and context of the infectious threat. Pathogen recognition and activation of innate immunity is mediated by members of the Toll-like receptor (TLR) family through detection of conserved microbial structures that are absent from the host. Experimental models of infection using TLR-deficient mice, as well as limited human studies, have clearly demonstrated the critical role of TLRs in host defense against most major groups of mammalian pathogens.

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“…[17][18][19][20][21] In addition to their critical roles in innate immunity, TLRs are essential in the orientation of the adaptive immune response through the induction of the Th 1 immune response. 22 Among the 10 human TLRs, TLR2 plays a key role in the immune responsiveness to peptidoglycans, 23,24 to lipoteichoic acid of Gram-positive bacteria, 25 to mycobacterial lipoproteins 26 and to leptospiral lipopolysaccharide (LPS). 27 That TLR2-deficient mice are highly susceptible to M. tuberculosis infection 28,29 suggests that mutations that affect TLR2 expression may impair host response to this pathogen.…”

Section: Introductionmentioning

confidence: 99%

The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans

et al. 2006

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The observation that Toll-like receptor (TLR)2-deficient mice are highly susceptible to mycobacteria suggests that mutations altering TLR2 expression may impair host response to Mycobacterium tuberculosis. We evaluated the association between guanine-thymine (GT) repeat polymorphism in intron II of the TLR2 gene and the presence of tuberculosis (TB) in Koreans. The numbers of GT repeats were determined by PCR and gene scans for 176 TB patients and 196 controls. The recombinant TLR2 promoter/exonI/exonII/intronII/luciferase constructs including three representative repeats: (GT) 13 , (GT) 20 , and (GT) 24 were transfected into K562 cells, and luciferase activities were estimated and compared. The expression of TLR2 on CD14 þ peripheral blood mononuclear cells (PBMC) from healthy volunteers were measured with flow cytometry. Genotypes with shorter GT repeats were more common among TB patients (49.4 vs 37.7%, P ¼ 0.02). This observation was confirmed among 82 other TB patients as a validation cohort. Shorter GT repeats were associated with weaker promoter activities and lower TLR2 expression on CD14 þ PBMCs. In conclusion, the development of TB disease in Koreans was associated with shorter GT repeats in intron II of the TLR2 gene. This association is correlated with lower expression of TLR2 through weaker promoter activity for genes with shorter GT repeats. Genes and Immunity (2006) 7, 150-155.

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Host Defense Mechanisms Triggered by Microbial Lipoproteins Through Toll-Like Receptors

Cited by 1,490 publications

References 40 publications

Peptidoglycan-associated lipoprotein ofAggregatibacter actinomycetemcomitansinduces apoptosis and production of proinflammatory cytokines via TLR2 in murine macrophages RAW 264.7in vitro

Peptidoglycan-associated lipoprotein ofAggregatibacter actinomycetemcomitansinduces apoptosis and production of proinflammatory cytokines via TLR2 in murine macrophages RAW 264.7in vitro

Toll-like receptors and their role in experimental models of microbial infection

The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans

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