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PubMed2002

The Lyme disease vaccine takes its toll.

Vaccination with Borrelia burgdorferi outer surface protein (Osp) A can induce a protective response against Lyme disease and serves as a model to understand the generation of protective immune responses against the spirochete. The innate response to pathogens is activated by specific Toll-like receptors (TLRs) that recognize distinct pathogen-associated molecular patterns. TLR2 is of particular interest for B. burgdorferi research because TLR2 recognizes several pathogen-associated molecular patterns, including lipoproteins. TLR2 may form heterodimers with TLR6 to identify diacylated lipoproteins, while TLR2 works in concert with TLR1 to recognize triacylated lipoproteins such as OspA. We will discuss the role of TLR1/2 in the development of responses to OspA in TLR1-and TLR2-deficient mice, and in selected individuals that received the OspA vaccine. While > 95% of human OspA-based Lyme disease vaccine recipients develop OspA antibodies, a very small group of individuals did not develop detectable humoral responses against OspA. We demonstrated that this hyporesponsiveness to OspA vaccination was associated with decreased cell surface expression of TLR1. Moreover, TLR1- and TLR2-deficient mice did not develop significant levels of OspA antibodies following vaccination with OspA, providing a correlation with human hyporesponsiveness to OspA. These data suggest that defects in the TLR1/2 signaling pathway are associated with an impaired ability to generate antibodies following immunization with OspA lipoprotein.

Animals↗
PubMed2006

Systemic inflammation and remote organ damage following bilateral femur fracture requires Toll-like receptor 4.

Extensive soft tissue injury and bone fracture are significant contributors to the initial systemic inflammatory response in multiply injured patients. Systemic inflammation can lead to organ dysfunction remote from the site of traumatic injury. The mechanisms underlying the recognition of peripheral injury and the subsequent activation of the immune response are unknown. Toll-like receptors (TLRs) recognize microbial products but also may recognize danger signals released from damaged tissues. Here we report that peripheral tissue trauma initiates systemic inflammation and remote organ dysfunction. Moreover, this systemic response to a sterile local injury requires toll-like receptor 4 (TLR4). Compared with wild-type (C3H/HeOuJ) mice, TLR4 mutant (C3H/HeJ) mice demonstrated reduced systemic and hepatic inflammatory responses to bilateral femur fracture. Trauma-induced nuclear factor (NF)-kappaB activation in the liver required functional TLR4 signaling. CD14-/- mice failed to demonstrate protection from fracture-induced systemic inflammation and hepatocellular injury. Therefore, our results also argue against a contribution of intestine-derived LPS to this process. These findings identify a critical role for TLR4 in the rapid recognition and response pathway to severe traumatic injury. Application of these findings in an evolutionary context suggests that multicellular organisms have evolved to use the same pattern recognition receptor for surviving traumatic and infectious challenges.

Alanine Transaminase↗
PubMed2005

Membrane-anchored CD14 is required for LPS-induced TLR4 endocytosis in TLR4/MD-2/CD14 overexpressing CHO cells.

Lipopolysaccharide (LPS) induces inflammatory activation through TLR4 (toll-like receptor-4)/MD-2 (myeloid differentiation-2)/CD14 (cluster of differentiation-14) complex. Although optimal LPS signaling is required to activate our innate immune systems against gram-negative bacterium, excessive amount of LPS signaling develops a detrimental inflammatory response in gram-negative bacterial infections. Downregulation of surface TLR4 expression is one of the critical mechanisms that can restrict LPS signaling. Here, we found that membrane-anchored CD14 is required for LPS-induced downregulation of TLR4 and MD-2 in CHO cells. Moreover, pretreatment of the cells with sterol-binding agent filipin reduced LPS-induced TLR4 downregulation, suggesting the involvement of caveolae-mediated endocytosis pathway. Involvement of caveolae in LPS-induced TLR4 endocytosis was further confirmed by immunoprecipitation. Thus, our data indicate that caveolae-dependent endocytosis pathway is involved in LPS-induced TLR4 downregulation and that this is dependent on membrane-anchored CD14 expression.

Animals↗
PubMed2002

Counteracting interactions between lipopolysaccharide molecules with differential activation of toll-like receptors.

We investigated counteracting interactions between the lipopolysaccharides (LPS) from Escherichia coli (Ec-LPS) and Porphyromonas gingivalis (Pg-LPS), which induce cellular activation through Toll-like receptor 4 (TLR4) and TLR2, respectively. We found that Ec-LPS induced tolerance in THP-1 cells to subsequent tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1beta) induction by Pg-LPS, though the reverse was not true, and looked for explanatory differential effects on the signal transduction pathway. Cells exposed to Pg-LPS, but not to Ec-LPS, displayed persisting expression of IL-1 receptor-associated kinase without apparent degradation, presumably allowing prolonged relay of downstream signals. Accordingly, cells pretreated with Pg-LPS, but not with Ec-LPS, were effectively activated in response to subsequent exposure to either LPS molecule, as evidenced by assessing nuclear factor (NF)-kappaB activity. In fact, Pg-LPS primed THP-1 cells for enhanced NF-kappaB activation and TNF-alpha release upon restimulation with the same LPS. This was a dose-dependent effect and correlated with upregulation of surface TLR2 expression. Furthermore, we observed inhibition of NF-kappaB-dependent transcription in a reporter cell line pretreated with Ec-LPS and restimulated with Pg-LPS (compared to cells pretreated with medium only and restimulated with Pg-LPS), but not when the reverse treatment was made. Although Pg-LPS could not make cells tolerant to subsequent activation by Ec-LPS, Pg-LPS inhibited Ec-LPS-induced TNF-alpha and IL-6 release when the two molecules were added simultaneously into THP-1 cell cultures. Pg-LPS also suppressed P. gingivalis FimA protein-induced NF-kappaB-dependent transcription in the 3E10/huTLR4 reporter cell line, which does not express TLR2. This rules out competition for common signaling intermediates, suggesting that Pg-LPS may block component(s) of the TLR4 receptor complex. Interactions between TLR2 and TLR4 agonists may be important in the regulation of inflammatory reactions.

Cell Line↗
PubMed2005

Interferon-gamma up-regulates toll-like receptor 4 and cooperates with lipopolysaccharide to produce macrophage-derived chemokine and interferon-gamma inducible protein-10 in human bladder cancer cell line RT4.

PURPOSE: Previously we have reported that RT4, a well differentiated human bladder cancer line, increases the expression of macrophage derived chemokine (MDC) and interferon (IFN)-gamma-inducible protein-10 (IP-10) in response to IFN-gamma and tumor necrosis factor (TNF)-alpha. In this study we examined the signal mechanisms for inducting these 2 chemokines in RT4 cells by lipopolysaccharide (LPS), IFN-gamma and TNF-alpha. MATERIALS AND METHODS: MDC and IP-10 expression was evaluated by sandwich enzyme-linked immunosorbent assay. Signal molecule activation was examined by Western blotting and electrophoretic mobility shift assay. The expression of toll-like receptor (TLR)-4 was analyzed by reverse transcriptase-polymerase chain reaction and flow cytometry. RESULTS: LPS did not induce RT4 cells to produce IP-10 and MDC. However, LPS plus IFN-gamma synergized the productions of the 2 chemokines. IFN-gamma up-regulated the expression of TLR-4, which is an LPS binding receptor. Although LPS and IFN-gamma alone marginally activated nuclear factor (NF)-kappaB but not AP-1, LPS plus IFN-gamma augmented NF-kappaB and AP-1. Specific inhibition of NF-kappaB and AP-1 pathways decreased the production of MDC and IP-10. Extracellular regulated kinase (ERK)1/2, an upstream signal of AP-1, was also responsive to LPS and/or IFN-gamma. TNF-alpha also activated NF-kappaB, AP-1 and ERK1/2. However, TNF-alpha plus IFN- gamma was associated with the activation of NF-kappaB but not of AP-1/ERK1/2 for the induction of MDC and IP-10. CONCLUSIONS: IFN-gamma enhances LPS for the induction of MDC and IP-10 through up-regulation of TLR-4, and the signal pathways of NF-kappaB and AP-1/ERK1/2. This mechanism may help us understand inflammatory responses of the bladder to localized bacterial infection.

Cell Line, Tumor↗
PubMed2006

Genetics of diabetic retinopathy.

Diabetes is rapidly increasing in frequency with an attendant toll of complications, including diabetic retinopathy. Although the underlying mechanisms remain elusive, genetic susceptibility is key to both types 1 and 2 diabetes and is increasingly recognized for its contribution to diabetic complications. In this article we review the evidence connecting genetic susceptibility to diabetic retinopathy. Elucidating the susceptibility genes and pathways should permit strategies to slow and reverse the troubling trends for the population, families, and individuals.

Diabetic Retinopathy↗
PubMed2006

Pathogenesis of spondyloarthritis: insights from synovial membrane studies.

Here, we review histopathologic studies of the cellular and molecular pathways of spondyloarthritis (SpA) synovial inflammation. In contrast with lymphocytes, specific macrophage subsets and polymorphonuclear cells selectively increase in SpA synovitis, correlate with global disease activity, decrease rapidly upon effective treatment with tumor necrosis factor (TNF)-alpha blockers, and serve as valuable biomarkers for treatment response in SpA. Functionally, increased Toll-like receptor triggering may be responsible for the proinflammatory response of these cells. Therefore, we propose that an exaggerated response of the innate immune system in genetically susceptible patients rather than a classic, lymphocyte-mediated autoimmune process is involved in the pathogenesis of SpA.

Humans↗
PubMed2003

[Pulmonary anti-Aspergillus defences].

The lung, constantly exposed to inhaled infectious particles, uses a very efficient immune system to insure sterility of the airways. It has to be tightly regulated for the tissues to be kept from its potentially deleterious effects. Pulmonary anti-Aspergillus defences are based upon the concurrent action of innate immunity, non specific but rapidly mobilisable, and of adaptative immunity. The former first consists in natural barriers, namely the respiratory epithelium and its antimicrobial peptides (complement, defensins, collectins). Then come the phagocytic cells (macrophages and neutrophils), but also the dendritic cells, able to stimulate adaptative responses through the presentation of antigens they have phagocytised ans processed. The Toll-like receptors are among the key ones involved in the recognition of fungal components. Chemokines have a crucial role for the recruitment, maturation and activation of neutrophils, while anti-inflammatory cytokines tightly influence T lymphocytes functional differentiation. These latter, cornerstones of the adaptative immunity, differentiate into two mutually exclusive pathways according to the type of cytokines which they produce. The Th1 one is largely protective in the context of Aspergillus, while the Th2 one is deleterious. However, a good cooperation between these 2 pathways is required for an efficient protection. Pulmonary anti-Aspergillus defences are multifactorial. Innate immunity is crucial but a capacity of the host to generate specific responses is also warranted.

Antibody Formation↗
PubMed2002

Dendritic cells and immunity to leishmaniasis and toxoplasmosis.

There is increased recognition that dendritic cells (DCs) are an important source of the IL-12 required to initiate protective immunity to protozoa, such as Leishmania and Toxoplasma. This article reviews the advances made in the last two years in understanding the pathways that lead to DC activation after infection with these organisms. Interestingly, there appear to be differences in the DC activation pathways utilized by these two intracellular protozoa which also may differ from the pathways utilized by bacteria.

Animals↗
PubMed2006

MyD88 deficiency results in tissue-specific changes in cytokine induction and inflammation in interleukin-18-independent mice infected with Borrelia burgdorferi.

Toll-like receptors (TLRs) play an important role in the control of infection with Borrelia burgdorferi. Deficiencies in TLR-2 or the shared TLR adapter molecule MyD88 have been shown to result in greatly increased bacterial burdens in mice. However, although in vitro studies have shown that the activation of TLR pathways by B. burgdorferi results in the release of inflammatory cytokines, studies in deficient mice have shown either no change or increased rather than decreased inflammation in infected animals. In this study, we looked at mechanisms to explain the increase in inflammation in the absence of MyD88. We found that MyD88-deficient mice infected with B. burgdorferi did not show increased inflammation at sites typically associated with Lyme disease (joints and heart). However, there was markedly increased inflammation in the muscles, kidneys, pancreas, and lungs of deficient animals. Muscle inflammation was typically seen perivascularly and perineuronally similar to that seen in infected humans. Chemotactic chemokines and cytokines were greatly increased in the muscle and kidneys of MyD88-deficient animals but not in the joints or heart tissue, suggesting that MyD88-independent pathways for recognizing B. burgdorferi and inducing these chemokines are present in the muscle and kidneys. Interleukin-18 signaling through MyD88 does not appear to play a role in either control of infection or inflammation.

Adaptor Proteins, Signal Transducing↗
PubMed2004

TLR4 is the signaling but not the lipopolysaccharide uptake receptor.

TLR4 is the primary recognition molecule for inflammatory responses initiated by bacterial LPS (endotoxin). Internalization of endotoxin by various cell types is an important step for its removal and detoxification. Because of its role as an LPS-signaling receptor, TLR4 has been suggested to be involved in cellular LPS uptake as well. LPS uptake was investigated in primary monocytes and endothelial cells derived from TLR4 and CD14 knockout C57BL/6 mice using tritiated and fluorescein-labeled LPS. Intracellular LPS distribution was investigated by deconvolution confocal microscopy. We could not observe any difference in LPS uptake and intracellular LPS distribution in either monocytes or endothelial cells between TLR4(-/-) and wild-type cells. As expected, CD14(-/-) monocytes showed a highly impaired LPS uptake, confirming CD14-dependent uptake in monocytes. Upon longer incubation periods, the CD14-deficient monocytes mimicked the LPS uptake pattern of endothelial cells. Endothelial cell LPS uptake is slower than monocyte uptake, LBP rather than CD14 dependent, and sensitive to polyanionic polymers, which have been shown to block scavenger receptor-dependent uptake mechanisms. We conclude that TLR4 is not involved in cellular LPS uptake mechanisms. In membrane CD14-positive cells, LPS is predominantly taken up via CD14-mediated pathways, whereas in the CD14-negative endothelial cells, there is a role for scavenger receptor-dependent pathways.

Animals↗
PubMed2006

Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus.

Antibodies (Abs) to RNA- and DNA-containing autoantigens are characteristic of systemic lupus erythematosus (SLE). We showed previously that Toll-like receptor (TLR) 9, recognizing DNA, is required for the spontaneous generation of DNA autoantibodies, but not for the development of lupus nephritis in susceptible mice. We report that lupus-prone mice deficient in TLR7, a receptor for ssRNA, failed to generate Abs to RNA-containing antigens (Ags) such as Smith (Sm) Ag. TLR9 and TLR7 also had dramatic effects on clinical disease in lupus-prone mice. In the absence of TLR9, autoimmune disease was exacerbated, lymphocytes and plasmacytoid DCs were more activated, and serum IgG and IFN-alpha were increased. In contrast, TLR7-deficient mice had ameliorated disease, decreased lymphocyte activation, and decreased serum IgG. These findings reveal opposing inflammatory and regulatory roles for TLR7 and TLR9, despite similar tissue expression and signaling pathways. These results have important implications for TLR-directed therapy of autoimmune disease.

Animals↗
PubMed2004

Identification of the molecular mechanism by which TLR ligation and IFN-gamma synergize to induce MIG.

Monokine Induced by Interferon-gamma (MIG), a CXC chemokine, is a potent inducer of T-cell chemotaxis and activation and has been implicated in the host response to viral infections and tumor immunity as well as in the pathogenesis of autoimmunity and transplant rejection. Although it is known that the Toll-Like Receptor-4 (TLR-4) ligand LPS synergizes with IFN-gamma to induce MIG expression in macrophages, the molecular mechanisms responsible for the synergy have yet to be elucidated. We determined that the marked synergy between LPS and IFN-gamma on MIG mRNA expression in mouse macrophages is a result of LPS-induced NF-kappaB and IFN-gamma-induced STAT. The synergy was not dependent on new protein synthesis, was independent of TNF-alpha, and occurred at the level of gene transcription. We identified 2 NF-kappaB sites located at -154 and -129 of the MIG promoter proximal to the gamma-responsive element that mediated this effect. Finally, we demonstrated that other TLR ligands (zymosan, double stranded RNA and CpG) synergized with IFN-gamma to induce MIG in an NF-kappaB dependent fashion. These data emphasize the ability of bacterial and viral products to activate/modify immune responses and promote adaptive T cell immunity through the NF-kappaB pathway.

Animals↗
PubMed2006

Necrotic neuronal cells induce inflammatory Schwann cell activation via TLR2 and TLR3: implication in Wallerian degeneration.

Schwann cells play an important role in peripheral nerve regeneration. Upon nerve injury, Schwann cells are activated and produce various proinflammatory cytokines and chemokines, resulting in the recruitment of macrophages and the phagocytosis of myelin debris. However, it is unclear how nerve injury induces Schwann cell activation. Recently, it was reported that necrotic cells induce immune cell activation via toll-like receptors (TLRs). This suggests that the TLRs expressed on Schwann cells may recognize nerve injury by binding to the endogenous ligands secreted by the damaged nerve, thereby inducing Schwann cell activation. To explore such a possibility, we stimulated rat Schwann cells with necrotic neuronal cells (NNC). The stimulation of Schwann cells with NNC induced the expression of various inflammatory mediators, including TNF-alpha and iNOS. Studies on the NNC-mediated intracellular signaling pathways revealed that p38 and JNK are involved in the NNC-mediated Schwann cell activation. In addition, NNC-induced proinflammatory gene expression was reduced in mouse Schwann cells derived from TLR2 or TLR3 knockout mice. In summary, these results suggest that necrotic neuronal cells induce inflammatory Schwann cell activation via TLR2 and TLR3, which might be involved in Wallerian degeneration upon peripheral nerve injury.

Animals↗
PubMedDate not supplied

Analysis of Tlr4-mediated LPS signal transduction in macrophages by mutational modification of the receptor.

In mouse macrophages (RAW 264.7 cells), toll-like receptor 4 (Tlr4) is a limiting factor in lipopolysaccharide (LPS) signal transduction. The expression of only 1-2 x 10(4) copies of recombinant Tlr4 per cell enhances sensitivity to LPS, shifting the EC50 by 30-fold to the left. Expression of the Tlr4(Lps-d) isoform of Tlr4 (found in C3H/HeJ mice) shifts the EC50 2600-fold to the right, essentially abolishing LPS responses. A truncated form of Tlr4, lacking a cytoplasmic domain, exerts only a weak inhibitory effect on signal transduction. Similarly, the normal or Tlr4(Lps-d) forms of protein lacking an ectodomain [corrected], cause modest inhibition of LPS signaling. Manipulations of Tlr4 structure and expression cause changes in LPS sensitivity that range over 3 to 4 orders of magnitude. These findings support the view that Tlr4 is an integral component of a solitary pathway for LPS signal transduction in macrophages and permit inferences related to the mechanism of signaling and its blockade.

Animals↗
PubMed2005

Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS.

A member of the IFN regulatory factor (IRF) family of transcription factors, IRF-4 is expressed in lymphocytes and macrophage/dendritic cells. Studies using IRF-4-deficient mice have revealed the critical roles of IRF-4 in lymphocyte responses. However, the role of IRF-4 in innate immune responses is not clearly understood. Here, we demonstrate that IRF-4 negatively regulates the production of proinflammatory cytokines by macrophages in response to Toll-like receptor (TLR) stimulation. Mice lacking IRF-4 are sensitive to LPS-induced shock, and their macrophages produce high levels of proinflammatory cytokines, including TNF-alpha and IL-6, in response to TLR ligands. The inhibitory role of IRF-4 in response to TLR stimulation was confirmed by the down-regulation of IRF-4 expression in normal macrophages by using the small interfering RNA technique and by the overexpression of IRF-4 in macrophage line RAW264.7. Activation of the important signaling pathways for cytokine production, NF-kappaB and JNK (c-Jun N-terminal kinase), was enhanced after LPS stimulation in IRF-4(-/-) macrophages. These results imply that IRF-4 negatively regulates TLR signaling and is inhibitory to the production of proinflammatory cytokines in response to TLR stimulation.

Animals↗
PubMed2003

How not to get bugged by bugs: mechanisms of cellular tolerance to microorganisms.

PURPOSE OF REVIEW: Advances in the characterization of the receptors and signaling pathways involved in the response to infection have led to a more detailed understanding of cellular tolerance to endotoxin and other microbial components. This review summarizes recent progress in the field, particularly in relation to the molecular mechanisms that underlie the development of tolerance to microorganisms. RECENT FINDINGS: The identification of Toll-like receptors as major sensors of microbial molecules has led to numerous studies of their function in tolerant cells. Decreased Toll-like receptor expression, altered interactions between the Toll-like receptors and intracellular signal transducers, and decreased expression or activity of downstream signaling molecules have all been implicated. Upregulation of specific proteins that inhibit Toll-like receptor signaling has also been described. Apart from these general mechanisms, special features of the intestinal microenvironment and its resident cells also contribute to making the gut hyporesponsive to microorganisms. SUMMARY: The application of gene knockout technology has highlighted the importance of macrophage tolerance in regulating innate immunity to microbial infection. Such studies have indicated that the failure of tolerance can lead to exaggerated inflammatory responses to intestinal bacteria, raising the possibility that defects in tolerance may be linked to conditions such as inflammatory bowel disease. Further characterization of this link will help in elucidating the pathogenesis of such conditions and in devising new approaches to treatment.

Journal Article↗
PubMed2005

Innate immune responses to infection.

The human host survives many infectious challenges in the absence of preexisting specific (adaptive) immunity because of the existence of a separate set of protective mechanisms that do not depend on specific antigenic recognition. These antigen-independent mechanisms constitute innate immunity. Antimicrobial peptides are released at epithelial surfaces and disrupt the membranes of many microbial pathogens. Toll-like receptors on epithelial cells and leukocytes recognize a range of microbial molecular patterns and generate intracellular signals for activation of a range of host responses. Cytokines released from leukocytes and other cells exhibit a vast array of regulatory functions in both adaptive and innate immunity. Chemokines released from infected tissues recruit diverse populations of leukocytes that express distinct chemokine receptors. Natural killer cells recognize and bind virus-infected host cells and tumor cells and induce their apoptosis. Complement, through the alternative and mannose-binding lectin pathways, mediates antibody-independent opsonization, phagocyte recruitment, and microbial lysis. Phagocytes migrate from the microcirculation into infected tissue and ingest and kill invading microbes. These innate immune mechanisms and their interactions in defense against infection provide the host with the time needed to mobilize the more slowly developing mechanisms of adaptive immunity, which might protect against subsequent challenges.

Animals↗