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PubMed2002

[Toll-like receptor and innate immunity in phylogenesis].

In protection against microbes, an organism recognizes the pathogen associated molecular pattern (PAMP) on microbes by pattern recognition receptor (PRR). Toll-like receptor is called innate immunity. A family of cell membrane receptor was found in recent years that can mediate innate immune responses through the activation of a series of immune-related genes. In phylogenesis, it is highly conservative. However, its functions are getting more diversified with the complication of the immune functions of organisms.

Animals↗
PubMed2006

Modulating responsiveness of human TLR7 and 8 to small molecule ligands with T-rich phosphorothiate oligodeoxynucleotides.

Toll-like receptors (TLR) 7 and 8 are closely related members of the TLR family of pathogen-associated molecular pattern recognition receptors and have an important function in activation of innate immune responses upon viral infection. TLR7 can be activated selectively by the guanosine analogue loxoribine, whereas the imidazoquinoline derivative Resiquimod (R-848) activates both TLR7 and TLR8. We demonstrate that co-incubation of R-848 with thymidine homopolymer oligodeoxynucleotides (ODN) significantly increased activity of R-848 on TLR8-expressing HEK 293 cells, but abolished TLR7-mediated signaling. Similarly, the combination of loxoribine and thymidine ODN redirected the stimulatory effect of loxoribine away from TLR7, and toward TLR8. This alteration in ligand specificity was demonstrated both in TLR-transfected HEK cells, and also in human PBMC, with a corresponding change in cytokine production away from IFN-alpha secretion by TLR7-expressing plasmacytoid DC and toward IL-12, TNF-alpha and IFN-gamma secretion by TLR8-expressing monocytes and NK cells. These results demonstrate an unexpected plasticity in the ligand specificities of TLR7 and TLR8, and suggest a novel sequence-selective interaction between these receptors and synthetic phosphorothioate ODN.

Cell Line↗
PubMed2002

CD14 signalling in lipid rafts: new ligands and co-receptors.

PURPOSE OF REVIEW: Lipid rafts on monocytes/macrophages provide a dynamic microenvironment for an integrated lipopolysaccharide receptor (CD14)-dependent clustering of a set of receptors involved in innate immunity and clearance of atherogenic lipoproteins. The purpose of this review is to summarize the recent advances in our understanding of CD14-dependent receptor clustering and its relevance in atherogenesis. RECENT FINDINGS: Upon binding of various ligands, CD14 as a multiligand pattern recognition receptor induces specific coassembly of additional receptors present on circulating monocytes. SUMMARY: The composition of the receptor cluster and thus the associated signalling pathways defines a ligand specific cellular response, linking endogenous and exogenous host defense to a common recognition platform in rafts.

Animals↗
PubMed2006

Molecular basis for invertebrate innate immune recognition of (1-->3)-beta-D-glucan as a pathogen-associated molecular pattern.

Innate immunity responds to various pathogen-associated molecular patterns (PAMPs) to evaluate the biological nature of foreign materials by using limited numbers of receptors. Analyses of interactions between PAMPs and its receptors are essential to understand the molecular basis regarding how we discriminate self and non-self materials. Upon infection of horseshoe crabs, an arthropod species, rapid hemolymph coagulation is induced to engulf invading microorganisms by a cascade-type reaction. The reaction is very sensitive to lipopolysaccharide and (1-->3)-beta-D-glucans on Gram-negative bacteria and fungi, respectively, and hence is utilized as assay reagents that detect and quantitate these PAMPs with a name of "limulus test." In this mini-review, recognition of (1-->3)-beta-D-glucans by a unique serine protease zymogen factor G of horseshoe crab is described. Molecular dissection and detailed kinetic analyses have revealed that multivalent binding to polymers of a simple target structure is one of the principles that allows stable and specific recognition of PAMPs by pattern recognition receptors in innate immunity.

Animals↗
PubMed2006

Toll-like receptors and innate immunity.

The innate immune system is an evolutionally conserved host defense mechanism against pathogens. Innate immune responses are initiated by pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Among them, Toll-like receptors (TLRs) are capable of sensing organisms ranging from bacteria to fungi, protozoa, and viruses, and play a major role in innate immunity. However, TLRs recognize pathogens either on the cell surface or in the lysosome/endosome compartment. Recently, cytoplasmic PRRs have been identified to detect pathogens that have invaded cytosols. In this review, we focus on the functions of PRRs in innate immunity and their downstream signaling cascades.

Animals↗
PubMed2006

Epithelial toll-like receptor 5 is constitutively localized in the mouse cecum and exhibits distinctive down-regulation during experimental colitis.

We recently demonstrated that the pattern recognition receptors (PRRs) toll-like receptor 2 (TLR2), TLR4, and CD14 are expressed in mouse colonic epithelium in a compartmentalized manner. Here we report the localization of TLR5, the receptor for bacterial flagellin, and its distinctive down-regulation during experimental colitis. Guts from normal BALB/c mice and those with dextran sodium sulfate (DSS)-induced colitis were compared. Each gut was divided into seven segments (stomach, small intestine [three parts], and colon [three parts]), and epithelial cells and crypt units were collected by scraping and EDTA treatment, respectively. Northern blotting showed that TLR5 mRNA was preferentially expressed in the epithelium of the proximal colon in normal mice. Laser capture microdissection coupled to reverse transcriptase PCR confirmed this localization. TLR5 protein expression reflected mRNA expression, as evidenced by Western blotting. In mice with acute colitis, inflammation occurred mainly in the distal colon. Interestingly, while TLR2, TLR4, and CD14 were up-regulated in the inflamed colon, TLR5 was down-regulated at both the mRNA and protein levels. Decreased TLR5 expression was more evident during chronic colitis. Additional in vitro studies using a mouse cell line, Colon-26, showed that gamma interferon (IFN-gamma) time- and dose-dependently down-regulates TLR5. In conclusion, epithelial cells, mainly in the proximal colon, constitutively express TLR5. TLR5 expression is down-regulated in vivo during acute and chronic DSS-induced colitis, in contrast to the expression of TLR2, TLR4, and CD14. The mechanism governing TLR5 regulation may therefore differ from that controlling other PRRs. Finally, IFN-gamma may be involved in down-regulating TLR5 expression.

Animals↗
PubMed1992

Invertebrate immunity: another viewpoint.

All vertebrates and invertebrates manifest self/non-self recognition. Any attempt to answer the question of adaptive significance of recognition must take into account the universality of receptor-mediated responses. These may take two forms: (1) rearranging, clonally distributed antigen-specific receptors that distinguish in the broadest sense between self and non-self, and non-self A from non-self B, latecomers on the evolutionary scene; (2) pattern recognition receptors, the earliest to evolve and still around, necessitating the requirement for induced second signals in T- and B-cell activation. Either strategy need not force upon invertebrates the organization, structure and adaptive functions of vertebrate immune systems. Thus, we can freely delve into the unique aspects of the primitive immune mechanisms of invertebrates. In contrast, using the opposite strategy which is still problematic, i.e. linking invertebrate and vertebrate defence, seems to give us an approach to universality that might eventually reveal homologous kinship.

Animals↗
PubMed2005

Nonopsonic phagocytosis of erythrocytes infected with ring-stage Plasmodium falciparum.

Ring-stage parasitized erythrocytes (RPEs) were demonstrated to interact with effector cells of the innate immune system. With receptor blockade studies and CD36-null macrophages, human and murine macrophages were shown to phagocytose RPEs through the pattern recognition receptor CD36. These in vitro data implicate scavenger receptors in the clearance of RPEs.

Animals↗
PubMed2004

Toll-like receptors: linking innate and adaptive immunity.

Detection of and response to microbial infections by the immune system depends largely on a family of pattern-recognition receptors called Toll-like receptors (TLRs). These receptors recognize conserved molecular products derived from various classes of pathogens, including Gram-positive and -negative bacteria, DNA and RNA viruses, fungi and protozoa. Recognition of ligands by TLRs leads to a series of signaling events resulting in induction of acute responses necessary to kill the pathogen. TLRs are also responsible for the induction of dendritic cell maturation, which is responsible and necessary for initiation of adaptive immune responses. Although TLRs control induction of adaptive immunity, it is not clear at this point how responses are appropriately tailored by individual TLRs to the advantage of the host.

Animals↗
PubMed2006

Identification and characterization of murine SCARA5, a novel class A scavenger receptor that is expressed by populations of epithelial cells.

Epithelia are positioned at a critical interface to prevent invasion by microorganisms from the environment. Pattern recognition receptors are important components of innate immunity because of their ability to interact with specific microbe-associated structures and initiate immune responses. Several distinct groups of receptors have been recognized. One of these, the scavenger receptors, has been classified into at least eight separate classes. The class A scavenger receptors are characterized by the presence of a collagen-like domain and include macrophage scavenger receptor type A (SR-A1 I/II, SCARA1) and MARCO (SCARA2). These receptors are known to make important contributions to host defense. Here, we identify a novel murine scavenger receptor, SCARA5, which has a structure typical of this class. The cDNA encodes 491 amino acids, which predict a type II protein that contains C-terminal intracellular, transmembrane, extracellular spacer, collagenous, and N-terminal scavenger receptor cysteine rich domains. Expression in Chinese hamster ovary cells confirmed that the receptor assembles as a homotrimer and is expressed at the plasma membrane. SCARA5-transfected cells bound Escherichia coli and Staphylococcus aureus, but not zymosan, in a polyanionic-inhibitable manner. Unlike other class A scavenger receptors, the receptor was unable to endocytose acetylated or oxidized low density lipoprotein. Quantitative RT-PCR and in situ hybridization demonstrate SCARA5 has a tissue and cellular distribution unique among class A scavenger receptors. Because of the restriction of SCARA5 transcripts to populations of epithelial cells, we propose that this receptor may play important roles in the innate immune activities of these cells.

Amino Acid Sequence↗
PubMed2003

Toll-like receptors and their function in innate and adaptive immunity.

Over the past 3 years our knowledge about how we sense the microbial world has been fundamentally changed. It has been known for decades that microbial products, such as lipopolysaccharide, lipoproteins, or peptidoglycan, have a profound activity on human cells. Whereas the structure of many different pathogenic microbial compounds has been extensively studied and characterized, the molecular basis of their recognition by the cells of the innate immune system remained elusive for a long time. It was Charles Janeway [Cold Spring Harb Symp Quant Biol 1989;54/1:1-13] who developed the idea of microbial structures forming pathogen-associated molecular patterns that would be recognized by pattern recognition receptors. The discovery of the family of Toll receptors in species as diverse as DROSOPHILA and humans, and the recognition of their role in distinguishing molecular patterns that are common to microorganisms have led to a renewed appreciation of the innate immune system. Moreover, it is now clear that the activation of the innate immune system through mammalian Toll-like receptors has also an instructive role for the responses of the adaptive immune response and, thus, may influence allergic diseases such as asthma.

Animals↗
PubMed2004

Disruption of membrane cholesterol stimulates MyD88-dependent NF-kappaB activation in immature B cells.

Agents that extract or sequester membrane cholesterol stimulate IkappaB degradation and lead to NF-kappaB activation in a subset of B cells. Although the extraction of cholesterol by methyl-beta-cyclodextrin is the most potent stimulus of NF-kappaB, other agents that sequester cholesterol have similar effects. B cells and B cell lines with an immature phenotype are significantly more sensitive to the effects of cholesterol perturbation than their mature B cell counterparts. NF-kappaB activation does not involve signaling from the B cell receptor complex. Instead, the disruption of membrane cholesterol activates NF-kappaB through a MyD88-dependent pathway involving the pattern recognition receptor, Toll-like receptor 4. We suggest that lipid raft microdomains may serve not only to orchestrate receptor signaling, but to sequester signaling components one from one another, which serves to prevent receptor-mediated signaling from occurring. A role for this process during B cell development is suggested.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Pentraxin 3 inhibits fibroblast growth factor 2-dependent activation of smooth muscle cells in vitro and neointima formation in vivo.

OBJECTIVE: The fibroblast growth factor (FGF)/FGF receptor system plays an important role in smooth muscle cell (SMC) activation. Long-pentraxin 3 (PTX3) is a soluble pattern recognition receptor with non-redundant functions in inflammation and innate immunity. PTX3 is produced by different cell types of the vessel wall, including SMCs. PTX3 binds FGF2 and inhibits its angiogenic activity on endothelial cells. We investigated the capacity of PTX3 to affect FGF2-dependent SMC activation in vitro and in vivo. METHODS AND RESULTS: When added to human coronary artery SMCs, human PTX3 inhibits cell proliferation driven by endogenous FGF2 and the mitogenic and chemotactic activity exerted by exogenous recombinant FGF2. Accordingly, PTX3 prevents (125)I-FGF2 interaction with FGF receptors on the same cells. Also, PTX3 overexpression after recombinant adeno-associated virus-PTX3 gene transfer inhibits human coronary artery SMC proliferation and survival promoted by FGF2 in vitro. Consistently, a single local endovascular injection of recombinant adeno-associated virus-PTX3 gene inhibits intimal thickening after balloon injury in rat carotid arteries. CONCLUSIONS: PTX3 is a potent inhibitor of the autocrine and paracrine stimulation exerted by FGF2 on SMCs. Local PTX3 upregulation may modulate SMC activation after arterial injury.

Animals↗
PubMed2004

CpG DNA as a potent inducer of mucosal immunity: implications for immunoprophylaxis and immunotherapy of mucosal infections.

Recent advances in immunology reveal that vertebrate innate immune systems use pattern-recognition receptors, of which the best characterized is the toll-like receptor (TLR) family, to specifically detect pathogen-associated molecular patterns (PAMPs) present in infectious agents. Based on this, use of synthetic PAMPs has attracted much interest for specific immunoprophylaxis and immunotherapy purposes. Among the PAMPs, immunostimulatory CpG DNA, a TLR9 ligand, displays promising potent immunostimulatory and adjuvanticity in different settings. In this review, recent developments in the use of CpG DNA for inducing immunity in the mucosal tissues will be highlighted.

Adjuvants, Immunologic↗
PubMed2005

Effects of the Escherichia coli toxin cytolysin A on mucosal immunostimulation via epithelial Ca2+ signalling and Toll-like receptor 4.

Epithelial cells are vital to sense the presence of bacteria, thereby initiating a proper innate immune response. This occurs via different mechanisms, e.g. recognition by pattern recognition receptors (TLR), or alteration of the cellular Ca2+ homeostasis. The Escherichia coli toxin cytolysin A (ClyA) is naturally delivered to target cells as active pore assemblies within outer membrane vesicles (OMVs), and we here investigate a possible role of ClyA-containing OMVs (ClyA+ (OMV)) for induction of proinflammatory responses via the above-mentioned mechanisms. We report that low, sublytic concentrations of ClyA+ (OMV) affect the Ca2+ homeostasis in epithelial cells by induction of slow, intracellular Ca2+ oscillations, while increased concentrations act cytolytically. Thus, ClyA belongs to the novel group of pore-forming toxins shown to elicit such biphasic responses. Ca2+ waves in the minute range have been shown to regulate gene transcription of, e.g. interleukin (IL)-6 and -8. While the periodicity of ClyA+ (OMV)-induced Ca2+ waves (22.9 +/- 0.9 min) fail to induce an IL-8 response, our data fit to the general concept of frequency-specific gene expression. Molecular investigations of the signal transduction pathway reveals that ClyA+ (OMV) utilize a different one as compared with those previously reported for other toxins causing Ca2+ waves. The ClyA protein per se and ClyA pore assemblies are non-immunogenic, while lipopolysaccharide present on the OMVs induces a TLR4-dependent proinflammatory response as expected. Additional membrane components of the OMV, e.g. OmpW, was also found to elicit proinflammatory responses that was independent of TLR4 and Ca2+ signalling.

Animals↗
PubMed2005

Toll-like receptor expression in the human nasopharyngeal tonsil (adenoid) and palantine tonsils: a preliminary report.

OBJECTIVE: The Waldeyer's ring, comprised of the nasopharyngeal tonsil (adenoid), the paired tubal tonsils, the paired palantine tonsils, and the lingual tonsil, is arranged in a circular orientation around the wall of the throat. This orientation allows direct contact between the tissues of the Waldeyer's ring and inhaled or ingested material, which may contain potential antigenic substances. Previous studies involving the tissues of the Waldeyer's ring have been focused on the adaptive immune system, with little consideration toward the innate immune system. Since studies have demonstrated that the adenoids and tonsils are capable of producing proinflammatory cytokines, we postulate that toll-like receptors (TLRs), which recognize components of pathogenic organisms, may be involved in the immune response in these tissues. TLRs are innate pattern recognition receptors, which produce proinflammatory cytokines and chemokines upon ligation. In this pilot study, we address expression of TLRs, which are vital components of the innate immune system, in adenoid and tonsil tissue. METHODS: To determine whether TLRs are expressed in the human adenoid and palantine tonsils, we utilized endpoint RT-PCR and real time RT-PCR. Endpoint PCR was performed on all tissue obtained from adenotonsillectomy patients. Real time RT-PCR was performed only on adenoid tissue. RESULTS: All of the ten TLRs examined are expressed in the adenoid and tonsil tissue with varying band intensities. TLR3, TLR7, TLR8, and TLR9 expression is highly variable between patients. CONCLUSIONS: TLRs are expressed in human adenoid and tonsil tissue, and may play a vital role in the immunological outcomes of these tissues.

Adenoids↗
PubMed2005

Plants and animals: a different taste for microbes?

Plants and animals can recognize potential pathogens by detecting pathogen-associated molecular patterns (PAMPs). Significant advances over the past few years have begun to unveil the molecular basis of PAMP perception by pattern recognition receptors (PRRs). Although these discoveries highlight common recognition strategies among higher eukaryotes, they also show differences with respect to the nature of the receptors involved and the exact molecular patterns recognized. This suggests a convergent evolution of microbe sensing by the innate immune systems of these various organisms.

Animals↗