Involvement of Toll-like Receptor (TLR) 2 and TLR4 in Cell Activation by Mannuronic Acid Polymers

Flo, Trude Helen; Ryan, Liv; Latz, Eicke; Takeuchi, Osamu; Monks, Brian G.; Lien, Egil; Halaas, Øyvind; Akira, Shizuo; Skjåk‐Bræk, Gudmund; Golenbock, Douglas T.; Espevik, Terje

doi:10.1074/jbc.m201366200

Cited by 179 publications

(108 citation statements)

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“…We and others have previously shown that TLR4 [23,42] as well as TLR5 [24,43] is also involved. Differential engagement of PRR involved in P. aeruginosa recognition could depend on the site or the time of infection and the prevailing microbial ligand.…”

Section: Discussionmentioning

confidence: 79%

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Synergistic regulation of Pseudomonas aeruginosa‐induced cytokine production in human monocytes by mannose receptor and TLR2

et al. 2009

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The immune response to pathogen is regulated by a combination of specific PRR, which are involved in pathogen recognition. Pseudomonas aeruginosa, a bacterium that causes life-threatening disease in immuno-compromised host, is recognized by distinct members of the TLR family. We have previously shown that viable P. aeruginosa bacteria are recognized by human monocytes mainly through TLR2. Using ligand-specific blocking antibodies, we herein show that the mannose receptor (MR), a phagocytic receptor for unopsonized P. aeruginosa bacteria, contributes equally to TLR2 in proinflammatory cytokine production by human monocytes in response to P. aeruginosa infection. Synergy of both receptors totally controls the immune response. Viable P. aeruginosa bacteria activate NF-jB and MAPK pathways and enhance TLR2-mediated signaling in MR-transfected human embryonic kidney 293 cells. Moreover, MR follows the same kinetics and colocalizes with TLR2 in the endosome during in vivo infection of human macrophages with P. aeruginosa. The studies provide the first demonstration of a significant role for MR, synergistic with TLR2, in activating a proinflammatory response to P. aeruginosa infection.Key words: Mannose receptor . NF-kB . Pseudomonas aeruginosa . TLR . TNF-a IntroductionThe innate immune system relies on a vast array of non-clonally expressed PRR to detect pathogens. PRR bind conserved molecular structures known as PAMP, which are shared by a large group of pathogens. PRR binding to microbial products elicits a signaling response within leukocytes to produce immune modulators in a PRR-dependent manner [1]. Proinflammatory cytokine production by monocyte/macrophage lineage orchestrates the immune response and predicts the outcome of infection. The overall immune response depends on the combination of engaged PRR and their specific ligands. This complexity allows the immune system not only to tailor its response to a specific pathogen but also to discriminate the site of infection or the microbial burden.Host recognition of PAMP may result in two entirely different outcomes. An appropriate response leads to the eradication of a microorganism [2], but an exaggerated inflammatory response may lead to illnesses such as sepsis and shock [3]. TLR are the best-characterized signal-generating receptors among the PRR. They initiate key inflammatory responses and shape adaptive immunity [4]. All human TLR ($11) are type I transmembrane glycoproteins containing an extracellular domain with leucinerich repeats responsible for ligand recognition and a cytoplasmic Toll/IL-1 receptor homology domain required for initiating signaling [5]. Working as homo-or heterodimers alone or with other PRR, they recognize a diverse array of microbial components in bacteria, fungi, parasites, and viruses. This includes lipid-based bacterial cell wall components such as LPS and lipopeptides, microbial protein components such as flagellin and profilin-like molecules, and nucleic acids such as dsRNA, ssRNA, and CpG DNA [6].TLR participate with additio...

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Section: Discussionmentioning

confidence: 79%

“…TLR2 has been reported to participate in recognition of multiple P. aeruginosa ligands, including lipoproteins [23,51], alginate [42], flagellin [52], and exoenzyme S [21]. TLR2 is an endocytic receptor [53] and has been reported to recruit phagosomes containing yeasts specifically to macrophage [36].…”

Section: Discussionmentioning

confidence: 99%

Synergistic regulation of Pseudomonas aeruginosa‐induced cytokine production in human monocytes by mannose receptor and TLR2

et al. 2009

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“…Soluble alginate rich in mannuronic acid (>86%) is able to induce TNF in monocytes through mechanisms involving CD14 [30] TLR2 and TLR4 [31]. Recently it was demonstrated that purified alginate rich in guluronic acid as used currently, did not activate TLRs [32].…”

Section: Cd11b Cd18 or Cd11c Blockagementioning

confidence: 99%

Alginate microsphere compositions dictate different mechanisms of complement activation with consequences for cytokine release and leukocyte activation

Ørning

Hoem

Coron

et al. 2016

Journal of Controlled Release

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The inflammatory potential of 12 types of alginate-based microspheres was assessed in a human whole blood model. The inflammatory potential could be categorized from low to high based on the four main alginate microsphere types; alginate microbeads, liquefied core poly-L-ornithine (PLO)-containing microcapsules, liquefied core poly-L-lysine (PLL)-containing microcapsules, and solid core PLLcontaining microcapsules. No complement or inflammatory cytokine activation was detected for the Ca/Ba alginate microbeads. Liquefied core PLO-and PLL-containing microcapsules induced significant fluid phase complement activation (TCC), but with low complement surface deposition (anti-C3c), and a low proinflammatory cytokine secretion, with exception of an elevated MCP-1(CCL2) secretion. The solid core PLL-containing microcapsules generated lower TCC but a marked complement surface deposition and significant induction of the proinflammatory cytokines interleukin (IL-1)β, TNF, IL-6, the chemokines IL-8 (CXCL8), and MIP-1α (CCL3) and MCP-1(CCL2).Inhibition with compstatin (C3 inhibitor) completely abolished complement surface deposition, leukocyte adhesion and the proinflammatory cytokines. The C5 inhibitions partly lead to a reduction of the proinflammatory cytokines. The leukocyte adhesion was abolished by inhibitory antibodies against CD18 and partly reduced by CD11b, but not by CD11c. Anti-CD18 significantly reduced the (IL-1)β, TNF, IL-6 and MIP-1α and anti-CD11b significantly reduced the IL-6 and VEGF secretion. MCP-1 was strongly activated by anti-CD18 and anti-CD11b. In conclusion the initial proinflammatory cytokine responses are driven by the microspheres potential to trigger complement C3 (C3b/iC3b) deposition, leukocyte activation and binding through complement receptor CR3 (CD11b/CD18).MCP-1 is one exception dependent on the fluid phase complement activation mediated through CR3.

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“…The preparation was characterized by quantitative PCR for the single copy wsp gene (29) and by immunofluorescent staining and counting on a FACSVantage flow cytometer (BD Biosciences). (30,31). The cells were maintained in DMEM (Cellgro) supplemented with 10% low endotoxin FCS (Atlanta Biologicals) in a 5% saturated CO 2 atmosphere at 37°C.…”

Section: Isolated Wolbachia Bacteriamentioning

confidence: 99%

Innate Immune Responses to Endosymbiotic Wolbachia Bacteria in Brugia malayi and Onchocerca volvulus Are Dependent on TLR2, TLR6, MyD88, and Mal, but Not TLR4, TRIF, or TRAM

Hise

Daehnel

Gillette‐Ferguson

et al. 2007

The Journal of Immunology

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106

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The discovery that endosymbiotic Wolbachia bacteria play an important role in the pathophysiology of diseases caused by filarial nematodes, including lymphatic filariasis and onchocerciasis (river blindness) has transformed our approach to these disabling diseases. Because these parasites infect hundreds of millions of individuals worldwide, understanding host factors involved in the pathogenesis of filarial-induced diseases is paramount. However, the role of early innate responses to filarial and Wolbachia ligands in the development of filarial diseases has not been fully elucidated. To determine the role of TLRs, we used cell lines transfected with human TLRs and macrophages from TLR and adaptor molecule-deficient mice and evaluated macrophage recruitment in vivo. Extracts of Brugia malayi and Onchocerca volvulus, which contain Wolbachia, directly stimulated human embryonic kidney cells expressing TLR2, but not TLR3 or TLR4. Wolbachia containing filarial extracts stimulated cytokine production in macrophages from C57BL/6 and TLR4−/− mice, but not from TLR2−/− or TLR6−/− mice. Similarly, macrophages from mice deficient in adaptor molecules Toll/IL-1R domain-containing adaptor-inducing IFN-β and Toll/IL-1R domain-containing adaptor-inducing IFN-β-related adaptor molecule produced equivalent cytokines as wild-type cells, whereas responses were absent in macrophages from MyD88−/− and Toll/IL-1R domain-containing adaptor protein (TIRAP)/MyD88 adaptor-like (Mal) deficient mice. Isolated Wolbachia bacteria demonstrated similar TLR and adaptor molecule requirements. In vivo, macrophage migration to the cornea in response to filarial extracts containing Wolbachia was dependent on TLR2 but not TLR4. These results establish that the innate inflammatory pathways activated by endosymbiotic Wolbachia in B. malayi and O. volvulus filaria are dependent on TLR2-TLR6 interactions and are mediated by adaptor molecules MyD88 and TIRAP/Mal.

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Involvement of Toll-like Receptor (TLR) 2 and TLR4 in Cell Activation by Mannuronic Acid Polymers

Cited by 179 publications

References 46 publications

Synergistic regulation of Pseudomonas aeruginosa‐induced cytokine production in human monocytes by mannose receptor and TLR2

Synergistic regulation of Pseudomonas aeruginosa‐induced cytokine production in human monocytes by mannose receptor and TLR2

Alginate microsphere compositions dictate different mechanisms of complement activation with consequences for cytokine release and leukocyte activation

Innate Immune Responses to Endosymbiotic Wolbachia Bacteria in Brugia malayi and Onchocerca volvulus Are Dependent on TLR2, TLR6, MyD88, and Mal, but Not TLR4, TRIF, or TRAM

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