The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors

Ozinsky, Adrian; Underhill, David; Fontenot, Jason D.; Hajjar, Adeline M.; Smith, Kelly D.; Wilson, Christopher; Schroeder, Lea; Aderem, Alan

doi:10.1073/pnas.250476497

Cited by 1,837 publications

(1,429 citation statements)

References 35 publications

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“…work has demonstrated that TLR2 is recruited to macrophage phagosomes containing either zymosan or IgG-opsonized sheep red blood cells [36,37], and similar to these observations, we also observed TLR2 enriched in P. aeruginosa endosome after 45 min of in vitro infection (Fig. 6B, i-iii).…”

Section: Mr Complexes With Tlr2 and Modulates Signaling Within Endosomessupporting

confidence: 89%

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: Mr Complexes With Tlr2 and Modulates Signaling Within Endosomessupporting

confidence: 89%

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

et al. 2009

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“…To investigate the receptors involved in NADPH oxidase activation, DC were stimulated with purified biglycan, glucan and Pam 3 CSK4, specific agonists of CD206, dectin-1 and TLR2, respectively [44][45][46]. We found that biglycan and Pam 3 CSK4, alone or in combination, did not activate ROS production (Fig.…”

Section: Dectin-1 Mediates Nadph Oxidase Activationmentioning

confidence: 88%

NADPH oxidase of human dendritic cells: Role in Candida albicans killing and regulation by interferons, dectin‐1 and CD206

et al. 2007

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Human monocyte-derived DC express the enzyme NADPH oxidase, responsible for ROS production. We show that Candida albicans did not activate NADPH oxidase in DC, and was poorly killed by these cells. However, Candida-killing activity increased upon DC stimulation with the NADPH oxidase activator PMA and was further enhanced by DC treatment with IFN-a or IFN-c. This fungicidal activity took place at high DC-to-Candida ratio, but decreased at low DC-to-yeast ratio, when Candida inhibited the NADPH oxidase by contrasting the assembly of the enzyme on DC plasma membrane. The NADPH oxidase inhibitor diphenyliodonium chloride abrogated the PMA-dependent DC candidacidal capacity. Engagement of b-glucan receptor dectin-1 induced NADPH oxidase activation in DC that was depressed by mannose-binding receptor CD206 costimulation. Candida was internalized by DC through mannose-binding receptors, but not through dectin-1, thus explaining why Candida did not elicit NADPH oxidase activity. Our results indicate that NADPH oxidase is involved in DC Candida-killing activity, which is increased by IFN. However, Candida escapes the oxidative damage by inhibiting NADPH oxidase and by entering DC through receptors not involved in NADPH oxidase activation. IntroductionDendritic cells (DC) play an important role in the initiation of immune responses [1][2][3][4]. In peripheral tissues, immature DC capture antigens by specialized receptors, undergo maturation and migrate to lymphoid organs where they present antigens to naive T cells [1][2][3][4]. Moreover, DC produce cytotoxic molecules limiting pathogen replication [5][6][7][8].Recently, we reported that human monocyte-derived DC express NADPH oxidase [9], the enzyme of leukocytes responsible for ROS production, whose activation requires the association between cytosolic (p47phox, p67phox, p40phox, p21rac) and membrane (gp91phox, p22phox) components [10,11]. ROS produced by NADPH oxidase of leukocytes are involved in pathogen killing, as demonstrated by the recurrent infections affecting individuals with chronic granulomatous disease, an inherited disorder in which the enzyme is not functional [10,11], but are also recognized as signaling molecules [12]. We previously showed that NADPH oxidase is not involved in DC differentiation, LPS-induced maturation, cytokine production and induction of T cell proliferation, but is required for DC killing of intracellular bacteria [9].The present study was undertaken to elucidate in more detail the regulation of DC NADPH oxidase activity and the role of this enzyme in pathogen-killing ability of ResultsRegulation of NADPH oxidase activity by IFN-a and IFN-cWe previously reported that PMA-stimulated human monocyte-derived DC release superoxide anion, which was nearly completely produced via NADPH oxidase activation [9]. Here we show that immature DC treatment with IFN-a or IFN-c enhanced the PMA-induced NADPH oxidase activity (Fig.1A, B). A surface phenotype analysis by flow cytometry demonstrated that this effect was not consequent to changes of DC...

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“…Based on our findings, it appears that in the presence of LPS contamination, activation of intracellular signaling pathways could involve interactions of the particle-associated LPS with LPS receptors on the cell surface [3,43,60]. In the absence of LPS contamination, adsorption and denaturation of serum proteins onto particle surfaces may function as ligands with LPS-like activity that could, in a similar fashion, interact with cell surface receptors to induce cell response.…”

Section: Discussionmentioning

confidence: 99%

The role of adsorbed endotoxin in particle‐induced stimulation of cytokine release

Cho

Shanbhag

Hong

et al. 2002

Journal Orthopaedic Research

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Numerous in vitro models have demonstraed the capacity of wear particles to stimulate the release of soluble pro‐inflammatory products with the ability to induce local bone resorption. Recent observations have demonstrated that binding of lipopolysaccharide (LPS) to particulate wear deris can significantly modulate the pattern of cell response in the in vitro models. These findings raise concerns over the possible role of LPS in the athogenesis of aseptic looseing after total joint replacements, and also indicates the importance of controlling for possible confounding effects of LPS contamination in the in vitro models used to study the reactive nature of wear debris. Our studies were undertaken to rigorously analyze the effects of particle‐associated LPS on cell responses and to assess the efficacy ofdifferent treatment protocols to inactivate LPS associated with different particulate materials. Particles of cobalt‐chrome alloy, titanium‐6‐aluminum‐4‐vanadium, titanium nitride and silica were pretreated with LPS and exposed to multiple treatment protocols. When cells were treated with „as‐received”︁ particles prepared by washing in ethanol, small amounts of TNF‐α, IL‐1β, and IL‐1α were detected. In contrast, all particle species pretreated with LPS produced marked increases in TNF‐α, IL‐1α, and IL‐1β release, as well as upregulation of corresponding mRNa levels even after ethanol washing. Boiling the LPS‐pretreated particles in 1% acetic acid or autoclaving and baking the particles also markedly reduced and in some instances abolished the effect of the LPS‐pretreatment. This indicates that LPS binds to the surface of particles of diverse composition and that the bound LPS is biologically active. Treatment protocols to inactivate particle‐associated LPS demonstrated significant differences in effcacy. When the most rigorous treatments were utilized, essentially all LPS activity could be eliminated. Particles treated with these methods retained some capacity to stimulated cytokine release, but activities were markedly reduced. These results provide further evidnce indicating that LPS contamination of particulate materials can markedly enhance their biological activity. This potential confounding effect needs to be carefully monitored and controlled in the in vitro model systems systems used to evaluate wear particles. Furthermore, the presence of particle‐associated endotoxin at the bone‐implant interface in vivo could markedly enhance the adverse biological activity of particulate wear debris. © 2002 Published by Elsevier Science Ltd. On behalf of Orthopaedic Research Society.

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The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors

Cited by 1,837 publications

References 35 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

NADPH oxidase of human dendritic cells: Role in Candida albicans killing and regulation by interferons, dectin‐1 and CD206

The role of adsorbed endotoxin in particle‐induced stimulation of cytokine release

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