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Results for “Receptors, Pattern Recognition”

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PubMed1999

Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products.

Toll-like receptors (TLRs) 2 and 4 are signal transducers for lipopolysaccharide, the major proinflammatory constituent in the outer membrane of Gram-negative bacteria. We observed that membrane lipoproteins/lipopeptides from Borrelia burgdorferi, Treponema pallidum, and Mycoplasma fermentans activated cells heterologously expressing TLR2 but not those expressing TLR1 or TLR4. These TLR2-expressing cells were also stimulated by living motile B. burgdorferi, suggesting that TLR2 recognition of lipoproteins is relevant to natural Borrelia infection. Importantly, a TLR2 antibody inhibited bacterial lipoprotein/lipopeptide-induced tumor necrosis factor release from human peripheral blood mononuclear cells, and TLR2-null Chinese hamster macrophages were insensitive to lipoprotein/lipopeptide challenge. The data suggest a role for the native protein in cellular activation by these ligands. In addition, TLR2-dependent responses were seen using whole Mycobacterium avium and Staphylococcus aureus, demonstrating that this receptor can function as a signal transducer for a wide spectrum of bacterial products. We conclude that diverse pathogens activate cells through TLR2 and propose that this molecule is a central pattern recognition receptor in host immune responses to microbial invasion.

Animals↗
PubMed2002

The class A macrophage scavenger receptor is a major pattern recognition receptor for Neisseria meningitidis which is independent of lipopolysaccharide and not required for secretory responses.

Macrophages (Mphi) play a key role in the pathogenesis of invasive meningococcal infections. The roles of two pattern recognition molecules, the Mphi scavenger receptor (SR-A) and Toll-like receptor 4 (TLR-4), have been investigated using bone marrow culture-derived Mphi (BMMphi). Surprisingly, a comparison of BMMphi from wild-type and SR-A knockout (SR-A(-/-)) mice showed that nonopsonic phagocytosis of meningococci was mediated almost exclusively via SR-A. Previous studies have demonstrated only a partial involvement of the receptor in the uptake of other bacteria, such as Escherichia coli. Interestingly, we also show that lipopolysaccharide (LPS) was not the ligand for the receptor on these organisms. Further study of the downstream events of SR-A-mediated ingestion of Neisseria meningitidis demonstrated that SR-A was not required for cytokine production. To determine the bacterial and host factors required to stimulate Mphi activation, we examined TLR-4-deficient Mphi from C3H/HeJ mice and LPS-deficient meningococci. TLR-4-deficient cells elaborated reduced amounts of tumor necrosis factor alpha, interleukin-12 (IL-12), and IL-10, even though ingestion via SR-A was unaffected in these cells. Similarly, although there was no change in SR-A-mediated ingestion of LPS-deficient meningococci, the mutant failed to stimulate a Mphi-dependent cytokine response. Thus, we show that Mphi SR-A mediates opsonin-independent uptake of N. meningitidis independently of lipid A and that this activity is uncoupled from the Mphi secretion of proinflammatory cytokines, which provides a basis for further investigation of the role of this receptor in meningococcal disease in humans.

Animals↗
PubMed2006

Chemokine production and pattern recognition receptor (PRR) expression in whole blood stimulated with pathogen-associated molecular patterns (PAMPs).

Recognition of conserved bacterial structures called pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), may lead to induction of a variety of "early immediate genes" such as chemokines. In the current study, we have in an ex vivo whole blood model studied the induction of the chemokines MIP-1alpha, MCP-1 and IL-8 by various PAMPs. The rate of appearance of Escherichia coli-Lipopolysaccharide (LPS) induced chemokines differed. The production of MIP-1alpha and IL-8 was after 1 h of stimulation significantly higher when compared to unstimulated whole blood, whereas MCP-1 was not significantly elevated until after 3 h. At peak levels the MIP-1alpha concentration induced by E. coli-LPS was 3-5-fold higher than MCP-1 and IL-8. By specific cell depletion, we demonstrated that all three chemokines were mainly produced by monocytes. However, the mRNA results showed that IL-8 was induced in both monocytes and granulocytes. The production of all three chemokines, induced by the E. coli-LPS and Neisseria meningitidis-LPS, was significantly inhibited by antibodies against CD14 and TLR4, implying these receptors to be of importance for the effects of LPS in whole blood. The chemokine production induced by lipoteichoic acid (LTA) and non-mannose-capped lipoarabinomannan (AraLAM) was, however, less efficiently blocked by antibodies against CD14 and TLR2. E. coli-LPS and LTA induced a dose-dependent increase of CD14, TLR2 and TLR4 expression on monocytes in whole blood. These data show that PAMPs may induce chemokine production in whole blood and that antibodies against PRRs inhibit the production to different extent.

Antibodies, Monoclonal↗
PubMed1997

The other side of scavenger receptors: pattern recognition for host defense.

Scavenger receptors bind modified lipoproteins and may play an important role both in normal and in pathological lipid metabolism. A number of different classes of scavenger receptors have been identified and several of these are multiligand receptors. Studies, both in vitro and in vivo, have indicated that at least some of these scavenger receptors may serve as pattern recognition receptors because they are able to bind a wide variety of pathogens. As a consequence, they may play key roles in innate immunity and host defense.

Animals↗
PubMed2006

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages.

Macrophage pattern recognition receptors (PRRs) play key roles in innate immunity, but they also may contribute to disease processes under certain pathological conditions. We recently showed that engagement of the type A scavenger receptor (SRA), a PRR, triggers JNK-dependent apoptosis in endoplasmic reticulum (ER)-stressed macrophages. In advanced atherosclerotic lesions, the SRA, activated JNK, and ER stress are observed in macrophages, and macrophage death in advanced atheromata leads to plaque necrosis. Herein, we show that SRA ligands trigger apoptosis in ER-stressed macrophages by cooperating with another PRR, Toll-like receptor 4 (TLR4), to redirect TLR4 signaling from prosurvival to proapoptotic. Common SRA ligands activate both TLR4 signaling and engage the SRA. The TLR4 effect results in activation of the proapoptotic MyD88-JNK branch of TLR4, whereas the SRA effect silences the prosurvival IRF-3-IFN-beta branch of TLR4. The normal cell-survival effect of LPS-induced TLR4 activation is converted into an apoptosis response by immunoneutralization of IFN-beta, and the apoptosis effect of SRA ligands is converted into a cell-survival response by reconstitution with IFN-beta. Thus, combinatorial signaling between two distinct PRRs results in a functional outcome-macrophage apoptosis that does not occur with either PRR alone. PRR-induced macrophage death may play important roles in advanced atherosclerosis and in other innate immunity-related processes in which the balance between macrophage survival and death is critical.

Animals↗
PubMed2004

Intracellular signaling and cytokine induction upon interactions of Porphyromonas gingivalis fimbriae with pattern-recognition receptors.

Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) of the innate immune system form functional receptor complexes that recognize and respond to pathogen-associated molecular patterns (PAMPs). Porphyromonas gingivalis is an important pathogen in human periodontitis and has also been implicated in atherosclerosis. A major virulence factor of this pathogen is the fimbriae, which function as a surface adhesin. Here we present evidence that fimbriae also constitute a predominant P. gingivalis proinflammatory molecule which activates the TLR signaling pathway resulting in induction of proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) and chemokines (IL-8) in monocytic cells. Although TLR2 and TLR4 mediate cellular activation in response to fimbriae, other PRRs, namely CD14 and CD11b/CD18, are involved in the recognition of fimbriae. We thus propose that fimbriae function as a PAMP which interacts with a PRR multi-receptor complex, where CD14 and CD11b/CD18 function as recruiting receptors and TLRs function as signaling receptors. In addition to cytokine induction, TLR activation by fimbriae also results in upregulation of the CD40, CD80, and CD86 costimulatory molecules in antigen-presenting cells, suggesting that fimbriae are sensed as a potential "danger" to the host immune system. Moreover, proinflammatory cytokine induction is attenuated upon repeated cellular stimulation with P. gingivalis fimbriae. This mechanism of tolerance induction which serves to mitigate excessive and potentially harmful inflammatory reactions appears to be due partly to fimbria-induced downregulation of the expression of interleukin-1 receptor-associated kinase-1 (IRAK-1), an important signaling intermediate of the TLR pathway. Understanding the molecular basis of how the host recognizes and responds to P. gingivalis fimbriae is essential for developing molecular approaches to control P. gingivalis-induced inflammatory responses in periodontal disease and perhaps atherosclerosis.

Cell Line↗
PubMed2000

Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus.

The innate immune system contributes to the earliest phase of the host defense against foreign organisms and has both soluble and cellular pattern recognition receptors for microbial products. Two important members of this receptor group, CD14 and the Toll-like receptor (TLR) pattern recognition receptors, are essential for the innate immune response to components of Gram-negative and Gram-positive bacteria, mycobacteria, spirochetes and yeast. We now find that these receptors function in an antiviral response as well. The innate immune response to the fusion protein of an important respiratory pathogen of humans, respiratory syncytial virus (RSV), was mediated by TLR4 and CD14. RSV persisted longer in the lungs of infected TLR4-deficient mice compared to normal mice. Thus, a common receptor activation pathway can initiate innate immune responses to both bacterial and viral pathogens.

Animals↗
PubMed2004

Induction of intracellular cytokine production in human monocytes/macrophages stimulated with ligands of pattern recognition receptors.

OBJECTIVE: This study addressed the role of the pattern recognition receptors (PRR), which recognize different molecular structures present on microorganisms, apoptotic, senescent and tumor cells, in the stimulation of human monocyte and monocyte-derived macrophages (MDM) for the production of intracellular cytokines. MATERIALS AND METHODS: Monocytes and MDM were stimulated with different ligands of scavenger receptors (SR) and mannose receptor (MR). Production of intracellular cytokines: tumor necrosis factor alpha (TNF alpha), interleukin 10 and 12 (IL-10, IL-12) was determined by flow cytometry following staining with anti-cytokine monoclonal antibodies (mAbs). RESULTS: The ligands of SR type A: fucoidan, polyguanylic acid (polyG), chemically modified low density lipoproteins (LDL), ligands of SR-B: native and chemically modified LDL, and ligand of mannose receptor (MR)-mannan induced strong expression of intracellular TNF alpha and weaker IL-10 in monocytes, while phosphatidylserine (PdS) was without effect. IL-12 was stimulated only by fucoidan and polyG. The induction of cytokine m-RNA generally followed the pattern and the magnitude of intracellular cytokine production. In MDM, intracellular TNF alpha and IL-12 expression was induced by mannan, native and modified LDL, but not other ligands. Expression of IL-10 was less pronounced and occurred following stimulation with fucoidan, polyG and modified, but not native, LDL. CONCLUSIONS: These results suggest that some PRR ligands may be involved in activation of monocytes/MDM for the production of mainly proinflammatory cytokines (TNF alpha, IL-12) implicating their role in the response to microbial and tumor invasion.

Cell Differentiation↗
PubMed2006

Role of the dual interaction of fungal pathogens with pattern recognition receptors in the activation and modulation of host defence.

Recognition of pathogen-associated molecular patterns (PAMPs) of microorganisms by pathogen recognition receptors induces signals responsible for the activation of genes important for an effective host defence, especially those of pro-inflammatory cytokines. Toll-like receptors (TLRs) and lectin-like receptors are the most important classes of pattern-recognition receptors. In addition to their effects on the activation of host defence, recent studies suggest that pathogenic fungi can modulate or interfere with the pattern recognition mechanisms of innate immunity, and can use pattern recognition receptors as mechanisms of escape from host defence. Two major recognition receptor-mediated escape mechanisms have been identified during infection with fungal pathogens: immunosuppression induced by activation of certain pattern recognition receptors, especially induction of IL-10 release through TLR2; and the blockade of TLR recognition by antigen modification during the germination of yeasts into hyphae. Thus, signals mediated by recognition receptors are not only beneficial to the host, but in certain situations can be used by pathogenic fungi to escape immune recognition and promote infection.

Animals↗
PubMed2006

Is/are pattern recognition receptor(s) for Staphylococcus aureus defective in atopic dermatitis?

It is known that Staphylococcus aureus induces the expression of human beta-defensin-2 (hBD-2), a well-characterized antimicrobial peptide, in keratinocytes. However, in spite of heavy colonization of atopic dermatitis (AD) skin lesions by S. aureus, these lesions have consistently been shown to contain low expression of hBD-2. The current article discusses various possible mechanisms for the low expression of hBD-2 in AD and raises the question whether the innate recognition of S. aureus by keratinocytes in AD is intact.

Dermatitis, Atopic↗
PubMed2005

Stimulation of innate immune responses by malarial glycosylphosphatidylinositol via pattern recognition receptors.

The glycosylphosphatidylinositol (GPI) anchor of Plasmodium falciparum is thought to function as a critical toxin that contributes to severe malarial pathogenesis by eliciting the production of proinflammatory responses by the innate immune system of mammalian hosts. Analysis of the fine structure of P. falciparum GPI suggests a requirement for the presence of both core glycan and lipid moieties in the recognition and signalling of parasite glycolipids by host immune cells. It has been demonstrated that GPI anchors of various parasitic protozoa can mediate cellular immune responses via members of the Toll-like family of pattern recognition receptors (TLRs). Recent studies indicate that GPI anchors of P. falciparum and other protozoa are preferentially recognized by TLR-2, involving the MyD88-dependent activation of specific signalling pathways that mediate the production of proinflammatory cytokines and nitric oxide from host macrophages in vitro. However, the contribution of malaria GPI toxin to severe disease syndromes and the role of specific TLRs or other pattern recognition receptors in innate immunity in vivo is only just beginning to be characterized. A better understanding of the molecular mechanisms underlying severe malarial pathogenesis may yet lead to substantial new insights with important implications for the development of novel therapeutics for malaria treatment.

Animals↗
PubMed2006

Identification of an antiangiogenic FGF2-binding site in the N terminus of the soluble pattern recognition receptor PTX3.

Long-pentraxin 3 (PTX3) is a soluble pattern recognition receptor with non-redundant functions in inflammation and innate immunity. PTX3 comprises a pentraxin-like C-terminal domain involved in complement activation via C1q interaction and an N-terminal extension with unknown functions. PTX3 binds fibroblast growth factor-2 (FGF2), inhibiting its pro-angiogenic and pro-restenotic activity. Here, retroviral transduced endothelial cells (ECs) overexpressing the N-terminal fragment PTX3-(1-178) showed reduced mitogenic activity in response to FGF2. Accordingly, purified recombinant PTX3-(1-178) binds FGF2, prevents PTX3/FGF2 interaction, and inhibits FGF2 mitogenic activity in ECs. Also, the monoclonal antibody mAb-MNB4, which recognizes the PTX3-(87-99) epitope, prevents FGF2/PTX3 interaction and abolishes the FGF2 antagonist activity of PTX3. Consistently, the synthetic peptides PTX3-(82-110) and PTX3-(97-110) bind FGF2 and inhibit the interaction of FGF2 with PTX3 immobilized to a BIAcore sensor chip, FGF2-dependent EC proliferation, and angiogenesis in vivo. Thus, the data identify a FGF2-binding domain in the N-terminal extension of PTX3 spanning the PTX3-(97-110) region, pointing to a novel function for the N-terminal extension of PTX3 and underlining the complexity of the PTX3 molecule for modular humoral pattern recognition.

Amino Acid Sequence↗
PubMed2026

Prophylactic Inhaled Pattern Recognition Receptor Agonists Reprogram Lung Epithelial Response and Prevent Type 2 Allergic Inflammation.

Prophylactic inhalation of the synergistic agents ODN M362 and Pam2CSK4 ("Pam2ODN") protects mice against allergic lung disease, including allergic inflammation caused by house dust mite (HDM). By preventing sensitization, Pam2ODN reduces HDM-induced eosinophilic and lymphocytic inflammation. How Pam2ODN affects interactions among lung epithelial cells, dendritic cells, and T cells to prevent eosinophilic lung inflammation remains unclear. In the present study, we show that a single inhaled dose of Pam2ODN before HDM sensitization reduces airway Th2 polarization without affecting Th1 or Treg responses. Furthermore, Pam2ODN pretreatment inhibits the recruitment of lung monocyte-derived dendritic cells (moDCs) and conventional Type 2 dendritic cells (DC2s), while preventing the HDM-induced decrease in conventional Type 1 dendritic cells (DC1s). Bulk RNA-seq of the whole lung reveals that Pam2ODN pretreatment restricts the expression of proinflammatory transcripts induced by HDM sensitization. This tolerogenic effect is also reflected at the single-cell level in lung epithelial cells, where proinflammatory transcripts, pathways, and chromatin accessibility are inhibited. These results indicate that Pam2ODN reprograms lung epithelial cells to attenuate allergen-induced Th2-promoting cytokines and DCs while maintaining the population of protective DC1s. These findings suggest a strategy to mitigate chronic allergic lung diseases.

Animals↗
PubMed2006

Antiviral signaling through pattern recognition receptors.

Viral infection is detected by the host innate immune system. Innate immune cells such as dendritic cells and macrophages detect nucleic acids derived from viruses through pattern recognition receptors (PRRs). Viral recognition by PRRs initiates the activation of signaling pathways that lead to production of type I interferon and inflammatory cytokines, which are important for the elimination of viruses. Two types of PRRs that recognize viral nucleic acids, Toll-like receptors (TLR) and RIG-I-like RNA helicases (RLH), have been identified. Of the TLRs, TLR3 recognizes viral double-stranded (ds) RNA, TLR7 and human TLR8 identify viral single-stranded (ss) RNA and TLR9 detects viral DNA. TLRs are located in endosomal compartments, whereas RLH are present in the cytoplasm where they detect viral dsRNA or ssRNA. Here we review the role of TLRs and RLHs in the antiviral innate immune response.

Animals↗
PubMed2005

[The effects of TNF alpha and IFN gamma on the expression of pattern recognition receptors on the surface of mouse alveolar macrophages].

OBJECTIVE: To investigate the effects of tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) on the expression of pattern recognition receptors (PRRs) on the surface of mouse alveolar macrophages. METHODS: Alveolar macrophages from mouse were cultured in DMEM supplemented with 10% (V/V) endotoxin-free calf serum. After the alveolar macrophages were stimulated with TNF alpha and IFN gamma (concentration, 20 ng/ml) for 3 h, 6 h and 12 h, the expression of PRRs, including cluster of differentiation 14 (CD14), scavenger receptor (SR), toll-like receptor 4 (TLR4), TLR2 and TLR9 mRNA and proteins were examined by RT-PCR and immunohistochemistry. RESULTS: The expressions of CD14, TLR2 and TLR9 receptors, which were related with cellular activation, were up-regulated by the stimulation of TNF alpha and IFN gamma (P < 0.05), while SR, which was related with cellular defense action, was down-regulated (P < 0.05). Although the expression of TLR4 was up-regulated, there was no statistical significance (P > 0.05). CONCLUSIONS: The cytokines such as TNF alpha and IFN gamma could also produce feedback regulation on the expression of PRRs at the levels of genes and proteins. Such regulation on the PRRs expression would be significant for further amplification of inflammation cascade and eventually leading to uncontrolled inflammation.

Animals↗
PubMed2000

Gram-negative bacteria-binding protein, a pattern recognition receptor for lipopolysaccharide and beta-1,3-glucan that mediates the signaling for the induction of innate immune genes in Drosophila melanogaster cells.

Pattern recognition receptors, non-clonal immune proteins recognizing common microbial components, are critical for non-self recognition and the subsequent induction of Rel/NF-kappaB-controlled innate immune genes. However, the molecular identities of such receptors are still obscure. Here, we present data showing that Drosophila possesses at least three cDNAs encoding members of the Gram-negative bacteria-binding protein (DGNBP) family, one of which, DGNBP-1, has been characterized. Western blot, flow cytometric, and confocal laser microscopic analyses demonstrate that DGNBP-1 exists in both a soluble and a glycosylphosphatidylinositol-anchored membrane form in culture medium supernatant and on Drosophila immunocompetent cells, respectively. DGNBP-1 has a high affinity to microbial immune elicitors such as lipopolysaccharide (LPS) and beta-1,3-glucan whereas no binding affinity is detected with peptidoglycan, beta-1,4-glucan, or chitin. Importantly, the overexpression of DGNBP-1 in Drosophila immunocompetent cells enhances LPS- and beta-1,3-glucan-induced innate immune gene (NF-kappaB-dependent antimicrobial peptide gene) expression, which can be specifically blocked by pretreatment with anti-DGNBP-1 antibody. These results suggest that DGNBP-1 functions as a pattern recognition receptor for LPS from Gram-negative bacteria and beta-1, 3-glucan from fungi and plays an important role in non-self recognition and the subsequent immune signal transmission for the induction of antimicrobial peptide genes in the Drosophila innate immune system.

Acute-Phase Proteins↗
PubMed2006

Pattern recognition receptors in companion and farm animals - the key to unlocking the door to animal disease?

The innate immune system is essential for host defence and is responsible for early detection of potentially pathogenic microorganisms. Upon recognition of microbes by innate immune cells, such as macrophages and dendritic cells, diverse signalling pathways are activated that combine to define inflammatory responses that direct sterilisation of the threat and/or orchestrate development of the adaptive immune response. Innate immune signalling must be carefully controlled and regulation comes in part from interactions between activating and inhibiting signalling receptors. In recent years, an increasing number of pattern recognition receptors (PRRs), including C-type lectin receptors and Toll-like receptors (TLRs), has been described that participate in innate recognition of microbes, especially through the so called pathogen-associated molecular patterns (PAMPs). Recent studies demonstrate strong interactions between signalling through these receptors. Whereas useful models to study these receptors in great detail in the murine and human system are now emerging, relatively little is known regarding these receptors in companion and farm animals. In this review, current knowledge regarding these receptors in species of veterinary relevance is summarised.

Animals↗