Lung cancer and Toll-like receptors

Lung carcinoma is one of the leading causes of death worldwide. It is a non-immunogenic cancer, resistant to immune surveillance. Toll-like receptors (TLRs) connect the innate to the adaptive immune system. Given that cancerous cells evade the immune system, the activation of TLRs could represent a potential target for cancer therapy. The induction of Th1-like and cytotoxic immunity by TLR signalling could lead to tumour cell death, resulting in tumour regression or arrest. However, basic research and clinical trials revealed that the activation of specific TLRs, such as TLR2, TLR4 and TLR9, do not have any anti-tumour activity in lung carcinoma. Increasing evidence suggests that TLRs are important regulators of tumour biology; however, little is known about their function in lung cancer. Thus, in order to develop new therapeutic approaches, further studies are needed to understand the connection between TLRs and lung cancer progression. This review focuses on the potential mechanisms by which TLR ligands can facilitate or not lung cancer and lung metastases establishment/progression.     

Regulation of mammalian defensin expression by Toll-like receptor-dependent and independent signalling pathways

The immune system consists of innate and adaptive immune responses. The innate immune system confers non-specific protection against a large number of pathogens, hence, serving as the first line of defence. The innate immune system utilizes Toll-like receptors (TLRs) to recognize and bind pathogen-associated molecular patterns (PAMPs). Binding of PAMPs leads to TLR activation, which, in turn, initiates MAPK- or NF-kappaB-dependent cascades that culminate in a proinflammatory response. This response involves the secretion of cytokines, chemokines and broad-spectrum antibacterial substances, such as defensins. Increased defensin synthesis is also mediated by the activation of receptors other than TLRs, such as NOD2, IL-17R and PAR-2. This review summarizes the recently characterized signalling pathways leading to increased defensin synthesis as well as the pathway by which defensins activate TLRs on immature dendritic and memory T cells. Thus, not only do defensins eliminate pathogens, but they also recruit the adaptive immune system in instances of infection and/or inflammation.     

Innate immunity: structure and function of TLRs

The innate immune system provides the first line of defence against infection. Through a limited number of germline-encoded receptors called pattern recognition receptors (PRRs), innate cells recognize and are activated by highly conserved structures expressed by large group of microorganisms called pathogen-associated molecular patterns (PAMPs). PRRs are involved either in recognition (scavenger receptors, C-type lectins) or in cell activation (Toll-like receptors or TLR, helicases and NOD molecules). TLRs play a pivotal role in cell activation in response to PAMPs. TLR are type I transmembrane proteins characterized by an intracellular Toll/IL 1 receptor homology domain that are expressed by innate immune cells (dendritic cells, macrophages, NK cells), cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, fibroblasts). In all the cell types analyzed, TLR agonists, alone or in combination with costimulatory molecules, induce cell activation. The crucial role played by TLR in immune cell activation has been detailed in dendritic cells. A TLR-dependent activation of dendritic cells is required to induce their maturation and migration to regional lymph nodes and to activate na?ve T cells. The ability of different cell types to respond to TLR agonists is related to the pattern of expression of the TLRs and its regulation as well as their intracellular localization. Recent studies suggest that the nature of the endocytic and signaling receptors engaged by PAMPs may determine the nature of the immune response generated against the microbial molecules, highlighting the role of TLRs as molecular interfaces between innate and adaptive immunity. In this review are summarized the main biological properties of the TLR molecules.     

MicroRNAs: the fine-tuners of Toll-like receptor signalling

Toll-like receptor (TLR) signalling must be tightly regulated to avoid excessive inflammation and to allow for tissue repair and the return to homeostasis after infection and tissue injury. MicroRNAs (miRNAs) have emerged as important controllers of TLR signalling. Several miRNAs are induced by TLR activation in innate immune cells and these and other miRNAs target the 3' untranslated regions of mRNAs encoding components of the TLR signalling system. miRNAs are also proving to be an important link between the innate and adaptive immune systems, and their dysregulation might have a role in the pathogenesis of inflammatory diseases.     

The role of Toll-like receptors in chronic inflammation

The role of Toll-like receptors (TLRs) in innate immunity and their ability to recognise microbial products has been well characterised. TLRs are also able to recognise endogenous molecules which are released upon cell damage and necrosis and have been shown to be present in numerous autoimmune diseases. Therefore, the release of endogenous TLR ligands during inflammation and consequently the activation of TLR signalling pathways may be one mechanism initiating and driving autoimmune diseases. An increasing body of circumstantial evidence implicates a role of TLR signalling in systemic lupus erythematosus (SLE), atherosclerosis, asthma, type 1 diabetes, multiple sclerosis, bowl inflammation and rheumatoid arthritis (RA). Although at present their involvement is not comprehensively defined. However, future therapies targeting individual TLRs or their signalling transducers may provide a more specific way of treating inflammatory diseases without global suppression of the immune system.     

Role of toll-like receptors in tissue repair and tumorigenesis

Toll-like receptors (TLRs) play a critical role in host defense from microbial infection. TLRs recognize conserved molecular structures produced by microorganisms and induce activation of innate and adaptive immune responses. The inflammatory responses induced by TLRs play an important role TLRs not only in host defense from infection, but also in tissue repair and regeneration. This latter function of TLRs can also contribute to tumorigenesis. Here we review recent progress in understanding the role of TLRs in cancer development.     

Toll-dependent and toll-independent innate antiviral immunity

Until recently, adaptive immunity and cytotoxic T cells were considered as the only essential components of the antiviral defence arsenal. Additional data that do not rule out the crucial role of these cells in the clearance of viral pathogens have, however, recently emerged. They indicate that innate immune cells such as macrophages, dendritic cells, gammadelta T cells as well as natural killer (NK) cells play a primordial role in this mechanism. It is now well established that innate immune cells can detect various pathogens (bacteria, viruses, fungi or parasites) very rapidly and respond to their presence through the activation of specific receptors. Once activated, these molecules trigger several signalling cascades that culminate in the establishment of very potent defence mechanisms. In addition, cytokines produced during this initial response are essential for the activation of the adaptive immune response which will add specificity and memory to the system. Among the innate immune receptors, attention has focused on the Toll-like receptors (TLR) and many reports indicate that some of the TLRs are clearly involved in defence against viral pathogens. However, new molecules, acting independently from any TLR, have recently been discovered. They define a second antiviral pathway which is presently the subject of intense research. In this article, we will review the role of the different molecules involved in each pathway within the framework of innate antiviral defence.     

Insights into the role of Toll-like receptors in modulation of T cell responses

The innate immune receptors, such as Toll-like receptors (TLRs), are intimately involved in the early sensing of invading microorganisms or their structural components. Engagement of TLRs with their ligands results in activation of several downstream intracellular pathways leading to activation of innate and adaptive immune system cells. It was initially thought that TLRs are primarily expressed by antigen-presenting cells (APCs), such as macrophages and dendritic cells, and that interactions between microbial ligands and TLRs in these cells will indirectly result in activation of cells of the adaptive immune system, especially T cells. However, it has now become evident that TLRs are also expressed by various T cell subsets, such as conventional αβT cells, regulatory T cells, and γδT cells as well as natural killer T cells. Importantly, it appears that at least in some of these T cell subsets, TLRs are functionally active, because stimulation of these cells with TLR agonists in the absence of APCs results in exertion of effector or regulatory functions of T cells. The present review attempts to summarize the recent findings related to TLR expression in different T cell subsets and the direct role of TLRs in the induction and regulation of T cell responses, including those responses that occur at mucosal surfaces. In addition, the potential use of TLR agonists for steering T cell responses as a prophylactic or therapeutic strategy in the context of infectious, allergic or autoimmune diseases is explored.     

How important are Toll‐like receptors for antimicrobial responses?

The innate immune system is the primary line of defence against invading pathogenic microbes. Toll-like receptors (TLRs) are a family of membrane receptors which play a pivotal role in sensing a wide range of invading pathogens including bacteria, fungi and viruses. TLR-deficient mice have provided us with immense knowledge on the functioning of individual TLRs. Dysregulation of TLR signalling is linked with a number of disease conditions. Disease models have helped show that targeting components of TLR signalling cascades could lead to novel therapies in the treatment of infectious diseases. In this review we focus on the evidence provided to date to explain just how important TLRs are in host defence against microbial pathogens.     

Sensing of bacteria: NOD a lonely job

Recognition of bacteria by the vertebrate innate immune system relies on detection of invariant molecules by specialized receptors. The view is emerging that activation of both Toll-like receptors (TLRs) and Nod-like receptors (NLRs) by different bacterial agonists is important in order to mount an inflammatory response in the host. Priming of cells with peptidoglycan and products that are sensed by cytosolic-localized members of the NLR family have a synergistic effect on TLR signalling and vice versa. Currently, the underlying molecular mechanisms of this cross-talk between NLR and TLR signalling are beginning to emerge. These reveal that the two sensing-systems are non-redundant in bacterial recognition and that their cross-talk plays an important role in immunological homeostasis.     

Toll-like receptor agonists synergize with CD40L to induce either proliferation or plasma cell differentiation of mouse B cells

In a classical dogma, pathogens are sensed (via recognition of Pathogen Associated Molecular Patterns (PAMPs)) by innate immune cells that in turn activate adaptive immune cells. However, recent data showed that TLRs (Toll Like Receptors), the most characterized class of Pattern Recognition Receptors, are also expressed by adaptive immune B cells. B cells play an important role in protective immunity essentially by differentiating into antibody-secreting cells (ASC). This differentiation requires at least two signals: the recognition of an antigen by the B cell specific receptor (BCR) and a T cell co-stimulatory signal provided mainly by CD154/CD40L acting on CD40. In order to better understand interactions of innate and adaptive B cell stimulatory signals, we evaluated the outcome of combinations of TLRs, BCR and/or CD40 stimulation. For this purpose, mouse spleen B cells were activated with synthetic TLR agonists, recombinant mouse CD40L and agonist anti-BCR antibodies. As expected, TLR agonists induced mouse B cell proliferation and activation or differentiation into ASC. Interestingly, addition of CD40 signal to TLR agonists stimulated either B cell proliferation and activation (TLR3, TLR4, and TLR9) or differentiation into ASC (TLR1/2, TLR2/6, TLR4 and TLR7). Addition of a BCR signal to CD40L and either TLR3 or TLR9 agonists did not induce differentiation into ASC, which could be interpreted as an entrance into the memory pathway. In conclusion, our results suggest that PAMPs synergize with signals from adaptive immunity to regulate B lymphocyte fate during humoral immune response.     

TLR family and viral infection

The immune system has been divided into innate and adaptive component, each of which has different roles and functions in defending the organism against foreign agents, such as bacteria and viruses. An important advance in our understanding of early events in microbial recognition and subsequent development of immune responses was the identification of Toll-like receptors (TLRs) as key molecules of the innate immune systems. The family of TLRs in vertebrates detects conserved structures found in a broad range of pathogens and triggers innate immune responses. At present, 11 members of the TLR family have been identified. A subset of TLRs recognize viral components and induce antiviral responses by producing type I interferons. Recent accumulating evidence has clarified signaling pathways triggered by TLRs in viral infection.     

Role of TLR4 in ethanol effects on innate and adaptive immune responses in peritoneal macrophages

Toll-like receptors (TLRs) play an important role in the innate immune response and these receptors link innate and adaptive responses. We have reported that ethanol modulates TLR4 receptors by activating or inhibiting its response. However, the role of TLRs in the effects of ethanol on the innate and adaptive responses during acute or chronic treatment is presently unknown. Peritoneal macrophages of wild-type and TLR4-deficient mice treated with acute ethanol (4?g?kg(-1), intraperitoneally) or chronic ethanol consumption (5 months) were used. Here we report how acute ethanol dose induces inflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-1β, macrophage inflammatory protein 1α (MIP-1α), interferon β1 and IL-12β) and chemokines (monocyte chemoattractant protein -1α and MIP-1α), and upregulates major histocompatibility complexes class I and II (MHC-I and -II), but inhibits the activation of the costimulatory molecules (CD86 and CD40), leading to the suppression of the CD4(+) T-cell proliferation in the macrophages of wild-type mice. Chronic ethanol consumption downregulates the number of F4/80(+) cells expressing MHC-I and -II and decreases CD4(+) T-cell activation in wild-type mice. Interestingly, elimination of TLR4 abolishes the effects of ethanol on the innate and the adaptive inflammatory response induced by both ethanol treatments in macrophages. Taken together, our findings support the role of TLR4 in the effects of ethanol on the immune system, and suggest that alterations in the function of this receptor might modulate the immune response induced by alcohol abuse.     

Endogenous toll‐like receptor ligands and their biological significance

Toll-like receptors (TLRs), a family of pattern recognition receptors, recognize and respond to conserved components of microbes and play a crucial role in both innate and adaptive immunity. In addition to binding exogenous ligands derived from pathogens, TLRs interact with endogenous molecules released from damaged tissues or dead cells and regulate many sterile inflammation processes. Putative endogenous TLR ligands include proteins and peptides, polysaccharides and proteoglycan, nucleic acids and phospholipids, which are cellular components, particularly extracellular matrix degradation products. Accumulating evidence demonstrates that endogenous ligand-mediated TLR signalling is involved in pathological conditions such as tissue injury, repair and regeneration; autoimmune diseases and tumorigenesis. The ability of TLRs to recognize endogenous stimulators appears to be essential to their function in regulating non-infectious inflammation. In this review, we summarize current knowledge of endogenous TLR ligands and discuss the biological significance of TLR signalling triggered by endogenous ligands in several sterile inflammation conditions.     

Toll-like receptors and their role in animal reproduction

Toll-like receptors (TLRs) are evolutionarily conserved innate immune receptors that recognize pathogen specific molecular pattern (PAMPs) in an efficient, non-self-reactive manner and initiate specific immune signaling that culminates in triggering antigen-specific adaptive responses. Different TLR genes in domestic animal species have been characterized and accumulating evidence from recent studies indicates an extended role for TLR signaling in reproductive physiology. In females, TLRs have been implicated in the regulation of ovulation, fertilization, gestation and parturition, as well as in pathological conditions such as endometritis and mastitis. In males, TLRs play a role in steroidogenesis and spermatogenesis. Use of TLR agonists has also been shown to be effective in the treatment of certain reproductive tract infections. Moreover, gene polymorphisms in TLRs have been associated with mastitis providing evidence that TLRs can potentially be exploited as markers in future breeding programs. The aim of this review is to provide a comprehensive treatise on role of TLRs in male and female reproductive physiology and associated pathology in domestic livestock.     

TLRs and chronic inflammation

After the discovery of Toll-like receptors (TLRs), innate immune mechanisms came back in the focus of scientific research. With more and more mechanisms of TLR biology known, it has become clear that these and also other innate immune receptors are not only of crucial importance in the immune response to invading pathogens, but also play a role in the homeostasis of commensal flora and in the response to stress and danger signals. In this respect, increasing evidence is found that inappropriate quantity or quality of TLR ligands or aberrant response to TLR activation plays a role in a variety of chronic inflammatory diseases. In this review, an overview of the currently known TLRs and their signaling pathways is given and reports about their expression and activation in chronic inflammatory diseases are recapitulated.     

Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism

Toll-like receptors (TLRs) have emerged as a major receptor family involved in non-self recognition. They have a vital role in triggering innate immunity and orchestrate the acquired immune response during bacterial and viral infection. However, the role of TLRs during infection with protozoan pathogens is less clear. Nevertheless, our understanding of how these parasitic microorganisms engage the host TLR signalling system has now entered a phase of rapid expansion. This Review describes recent insights into how parasitic protozoans are sensed by TLR molecules, and how the TLR system itself can be targeted by these microbial pathogens for their own survival.     

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.