Therapeutic targeting of Toll-like receptors: a review of Toll-like receptors and their signaling pathways in psoriasis

Introduction: Expression of various Toll-like receptors (TLR) in keratinocytes (KCs) has offered new insights into the pathogenesis of psoriasis. When plasmacytoid dendritic cells (pDCs) are scarce in established psoriatic lesions, KCs take the responsibility to secrete IFN type 1 through TLR9 activation. Antagonists of TLR7 and TLR8 and anti-IL-12/IL-23 substances have shown promising results in treating psoriasis.

Areas covered: References in this study were extracted from Scopus, PubMed and Embase databases by the search term: (‘Toll-Like Receptors’ OR ‘TLR’) AND (‘Psoriasis’ OR ‘Arthritis, Psoriatic’ OR ‘PsA’).

Expert commentary: As the prevailing cell type, KCs play a major role in the maintenance of psoriatic lesions. By specific upregulation of IL-36 R, KCs can start the IL-23/IL-12 axis, leading to production of major culprits of psoriatic phenotype IL-17 and IL-22. Targeting IL-36 R could be considered as a new therapeutic target to eliminate cutaneous manifestations of psoriasis.     

Important aspects of Toll-like receptors, ligands and their signaling pathways

Due to the rapid increase of new information on the multiple roles of Toll-like receptors (TLRs), this paper reviews several main properties of TLRs and their ligands and signaling pathways. The investigation of pathogen infections in knockout mice suggests that specific TLRs play a key role in the activation of immune responses. Although the investigation of TLR biology is just beginning, a number of important findings are emerging. This review focuses on the following seven aspects of this emerging field: (a) a history of TLR and ligand studies; (b) the molecular basis of recognition by TLRs: TLR structures, pathogen-associated molecular pattern binding sites, TLR locations and functional responses; (c) cell types in TLR expression; (d) an overview of TLRs and their ligands: expression and ligands of cell-surface TLRs and of intracellular TLRs; (e) TLR-signaling pathways; (f) discussion: TLRs control of innate and adaptive systems; the trafficking of intracellular TLRs to endolysosomes; investigation of TLRs in regulating microRNA; investigation of crystal structure of TLRs with ligand binding; incidence of infectious diseases associated with single nucleotide polymorphisms (SNPs) in TLR genes; risk of cancer related to SNPs in TLR genes; TLR-ligand mediated anti-cancer effects; and TLR-ligand induced chronic inflammation and tumorigenesis; and (g) conclusions.     

Translational mini-review series on Toll-like receptors: networks regulated by Toll-like receptors mediate innate and adaptive immunity

The Toll-like receptor (TLR) family provide key components of mammalian immunity and are part of the earliest surveillance mechanisms responding to infection. Their activation triggers the innate immune response, and is crucial to the successful induction of Th1/Th2-phenotyped adaptive immunity. Innate immunity was long considered to be non-specific and somewhat simple compared to adaptive immunity, mediated via the engulfment and lysis of microbial pathogens by phagocytic cells such as macrophages and neutrophils, and involving no complex protein-protein interactions. The emergence of the TLR field has contributed to a revision of our understanding, and innate immunity is now viewed as a highly complex process, in line with adaptive immunity. This review will give a brief overview of our current knowledge of TLR biology, and will focus on TLRs as key components in complex networks that activate, integrate and select the appropriate innate and adaptive immune responses in the face of immunological danger.     

E3 ubiquitin ligases Pellinos as regulators of pattern recognition receptor signaling and immune responses

Pellinos are a family of E3 ubiquitin ligases discovered for their role in catalyzing K63-linked polyubiquitination of Pelle, an interleukin-1 (IL-1) receptor-associated kinase homolog in the Drosophila Toll pathway. Subsequent studies have revealed the central and non-redundant roles of mammalian Pellino-1, Pellino-2, and Pelino-3 in signaling pathways emanating from IL-1 receptors, Toll-like receptors, NOD-like receptors, T- and B-cell receptors. While Pellinos ability to interact with many signaling intermediates suggested their scaffolding roles, recent findings in mice expressing ligase-inactive Pellinos demonstrated the importance of Pellino ubiquitin ligase activity. Cell-specific functions of Pellinos have emerged, e.g. Pellino-1 being a negative regulator in T lymphocytes and a positive regulator in myeloid cells, and details of molecular regulation of receptor signaling by various members of the Pellino family have been revealed. In this review, we summarize current information about Pellino-mediated regulation of signaling by pattern recognition receptors, T-cell and B-cell receptors and tumor necrosis factor receptors, and discuss Pellinos roles in sepsis and infectious diseases, as well as in autoimmune, inflammatory, and allergic disorders. We also provide our perspective on the potential of targeting Pellinos with peptide- or small molecule-based drug compounds as a new therapeutic approach for septic shock and autoimmune pathologies.     

Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity

Summary: Toll-like receptors (TLRs) detect infections by highly conserved components of pathogens that are either not present in our own cells or are normally sequestered in cellular compartments that are inaccessible to the TLRs. Most TLRs are expressed on the cell surface, where they have been shown to detect pathogen-expressed molecules such as lipopolysaccharides and lipopeptides. A subset of TLRs, including TLR3, TLR7, TLR8, and TLR9, are expressed intracellularly within one or more endosomal compartments and detect nucleic acids. Because pathogen and host nucleic acids have very similar structures, these endosomal TLRs may face an extra challenge to induce anti-pathogen immune responses while avoiding the induction of autoimmune diseases. With the rapid growth in understanding of the biology of the TLRs has come an increasing awareness of their effects on autoimmunity, several aspects of which are the focus of this review. First, recent studies have revealed an inappropriate activation of TLR7, TLR8, and TLR9 in systemic lupus erythematosus and several other autoimmune diseases. Secondly, the potential for therapeutic development of TLR antagonists is considered. Finally, with the rapid progress in the development of therapeutic agonists for the TLRs, there is accompanying attention to the theoretical possibility that such therapy may induce autoimmunity or autoimmune diseases.     

CD4 + T CELL MATTERS IN TUMOR IMMUNITY

CD4 + T cells have been shown to be able to affect tumor growth through both direct and indirect means. In addition, a requirement has been demonstrated for CD4 + T cells in the regulation and induction of T cell memory, and CD4 + suppressor T cells have been identified, stressing a role for CD4 + T cells in the induction and maintenance of antitumor immune responses. A review of the involvement of CD4 + T cells at different stages of tumor immunity is provided, and based on these data we discuss how CD4 + T cell response induction could be incorporated into tumor immunotherapy strategies. dendritic cells suppressor T cells T cell memory CD4 + T cells tumor immunology     

Viral sensors: diversity in pathogen recognition

Summary:  Innate sensors of viral infection detect viral products and initiate the signal cascades that lead to the antiviral response. Several proteins have been identified to play a role in this process, mostly members of the Toll-like receptor and retinoic acid-inducible gene I-like receptor families. These receptors have been demonstrated to function in part by recognizing a diverse yet unique repertoire of nucleic acid substrates. Upon recognition of their ligands, these sensors activate distinct signaling pathways that lead to the secretion of type I interferon and inflammatory cytokines. It remains to be seen, however, if these sensors are redundant or whether each serves a unique function. In this work, we review the current knowledge of viral sensors, speculate on how they may function in vivo , and explore the potential reasons for their diversity.     

Toll-like receptor signaling in neonatal sepsis and inflammation: a matter of orchestration and conditioning

Altered neonatal Toll-like receptor (TLR) function is hypothesized to contribute to the heightened susceptibility to infection and perpetuated inflammation in term and preterm neonates, clinically evident in neonatal sepsis and increased rates of inflammatory disorders. Current data indicate that basal TLR expression in term neonates equals adult expression patterns, while expression in preterm infants seems to increase, depending on gestational age. Regarding TLR signaling, some studies suggest TLR incompetence in neonates associated with impaired pro-inflammatory responses, others describe neonatal TLR function well developed and allude to its hyper-inflammation tendency. We discuss the competing positions and considerable limitations of research approaches and conclude that neonatal innate immunity is not generally less able to respond to TLR stimulation. Moreover, we describe pre-conditioning factors other than immaturity having a comparable impact. In the long term, better understanding of the complex interplay of pre- and postnatal conditions and maturation-dependent neonatal TLR function may provide new therapeutic approaches.     

Mammalian Toll-like receptors: to immunity and beyond

Toll-like receptors (TLRs) constitute an archetypal pattern recognition system. Their sophisticated biology underpins the ability of innate immunity to discriminate between highly diverse microbial pathogens and self. However, the remarkable progress made in describing this biology has also revealed new immunological systems and processes previously hidden to investigators. In particular, TLRs appear to have a fundamental role in the generation of clonal adaptive immune responses, non-infectious disease pathogenesis and even in the maintenance of normal mammalian homeostasis. Although an understanding of TLRs has answered some fundamental questions at the host-pathogen interface, further issues, particularly regarding therapeutic modulation of these receptors, have yet to be resolved.     

Toll-like receptors: cellular signal transducers for exogenous molecular patterns causing immune responses

Innate immunity initiates protection of the host organism against invasion and subsequent multiplication of microbes by specific recognition. Germ line-encoded receptors have been identified for microbial products such as mannan, lipopeptide, peptidoglycan (PGN), lipoteichoic acid (LTA), lipopolysaccharide (LPS), and CpG-DNA. The Drosophila Toll protein has been shown to be involved in innate immune response of the adult fruitfly. Members of the family of Toll-like receptors (TLRs) in vertebrates have been implicated as pattern recognition receptors (PRRs). Ten TLRs are known and six of these have been demonstrated to mediate cellular activation by distinct microbial products. TLR4 has been implicated as activator of adaptive immunity, and analysis of systemic LPS responses in mice led to the identification of LPS-resistant strains instrumental in its identification as a transmembrane LPS signal transducer. Structural similarities between TLRs and receptor molecules involved in immune responses such as CD14 and the IL-1 receptors (IL-1Rs), as well as functional analysis qualified TLR2 as candidate receptor for LPS and other microbial products. Targeted disruption of the TLR9 gene in mice led to identification of TLR9 as CpG-DNA signal transducer. Involvement of TLR5 in cell activation by bacterial flagellin has been demonstrated. Further understanding of recognition and cellular signaling activated through the ancient host defense system represented by Toll will eventually lead to means for its therapeutic modulation.     

Translational mini-review series on Toll-like receptors: recent advances in understanding the role of Toll-like receptors in anti-viral immunity

(TLRs) respond to pathogens to initiate the innate immune response and direct adaptive immunity, and evidence to date suggests that they have a role in the detection of viruses. Many viral macromolecules have been shown to activate anti-viral signalling pathways via TLRs, leading to the induction of cytokines and interferons, while viruses also have means of not only evading detection by TLRs, but also of subverting these receptors for their own purposes. This review discusses the role of TLRs in the context of other known viral detection systems, and examines some of the often surprising results from studies using mice deficient in TLRs and their adaptors, in an attempt to unravel the particular contribution of TLRs to anti-viral immunity.     

Sensing of Mycobacterium tuberculosis and consequences to both host and bacillus

Mycobacterium tuberculosis (Mtb), the primary causative agent of human tuberculosis, has killed more people than any other bacterial pathogen in human history and remains one of the most important transmissible diseases worldwide. Because of the long-standing interaction of Mtb with humans, it is no surprise that human mucosal and innate immune cells have evolved multiple mechanisms to detect Mtb during initial contact. To that end, the cell surface of human cells is decorated with numerous pattern recognition receptors for a variety of mycobacterial ligands. Furthermore, once Mtb is ingested into professional phagocytes, other host molecules are engaged to report on the presence of an intracellular pathogen. In this review, we discuss the role of specific mycobacterial products in modulating the host's ability to detect Mtb. In addition, we describe the specific host receptors that mediate the detection of mycobacterial infection and the role of individual receptors in mycobacterial pathogenesis in humans and model organisms.     

Cytosolic d-type CpG-oligonucleotides induce a type I interferon response by activating the cGAS-STING signaling pathway

Cytosolic DNA receptor cyclic GMP-AMP (cGAMP) synthase (cGAS) has been shown to be critically involved in the detection of cytosolic, self- and non-self-DNA, initiating a type I IFN response through the adaptor protein Stimulator of Interferon Genes (STING) and interferon regulatory factor 3 (IRF3). Current studies propose that canonical binding of dsDNA by cGAS depends on DNA length, but not on base sequence. In contrast, activation of TLR9 is sequence dependent. It requires unmethylated CpG dinucleotides in microbial DNA, which is mimicked by synthetic oligodeoxynucleotides (ODN). Here, we provide evidence that d -type ODN (D-ODN), but not K-type ODN (K-ODN), bind to human cGAS and activate downstream signaling. Transfection of D-ODN into a TLR9-deficient, human monocytic cell line (THP-1) induced phosphorylation of IRF3 and secretion of IFN. This response was absent in cells with CRISPR/Cas9-mediated cGAS- or STING-deficiency. Utilizing a protein pulldown approach, we further demonstrate direct binding of D-ODN to cGAS. Induction of a type I IFN response by D-ODN was confirmed in human primary monocytes and monocyte-derived macrophages. These results are relevant to our understanding of self–nonself-discrimination by cGAS and to the pharmacologic effects of ODN, which currently are investigated in clinical studies.     

Differential constitutive and cytokine-modulated expression of human Toll-like receptors in primary neutrophils, monocytes, and macrophages

Human Toll-like receptors (TLRs) comprise a family of proteins that recognizes pathogen-associated molecular patterns (PAMPs) and initiates host innate immune responses. Neutrophils, monocytes, and macrophages are critical cellular components of the human innate immune system. Proinflammatory cytokines, such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interferon-gamma (IFN-gamma), have been shown to up-regulate microbicidal activity in these effector cells of innate immunity. Currently, the cellular and molecular mechanisms responsible for these effects are not completely understood. We hypothesized that these cytokines may up-regulate TLR expression as a mechanism to facilitate microbial recognition and augment the innate immune response. Using quantitative realtime rt-PCR technology, we examined constitutive expression of TLR2, TLR4, TLR5, and TLR9 mRNA and the effects of G-CSF, GM-CSF, M-CSF, and IFN-gamma on TLR mRNA expression in purified populations of normal human neutrophils, monocytes, and monocyte-derived macrophages. Relative constitutive expression of TLR2, TLR4, and TLR9 was similar in neutrophils and monocytes. Constitutive expression of TLR5 was less in neutrophils compared to monocytes. Constitutive expression of TLR4 was greater and that of TLR9 lower in monocyte-derived macrophages compared to monocytes. Of the cytokines examined, IFN-gamma and GM-CSF caused the greatest effects on TLR expression. IFN- gamma up-regulated TLR2 and TLR4 in neutrophils and monocytes. GM-CSF up-regulated expression of TLR2 and TLR4 in neutrophils and TLR2 in monocytes. TLR5 was down-regulated by inflammatory cytokines in monocytes. These results suggest a potential role for IFN- gamma and/or GM-CSF as therapeutic immunomodulators of the host defense to infection.     

Effects of air pollutants on innate immunity: the role of Toll-like receptors and nucleotide-binding oligomerization domain-like receptors

Interactions between exposure to ambient air pollutants and respiratory pathogens have been shown to modify respiratory immune responses. Emerging data suggest key roles for Toll-like receptor (TLR) and nucleotide-binding oligomerization domain-like receptor (NLR) signaling in pathogen-induced immune responses. Similarly, immune responses elicited by exposure to air pollutants are mediated by specific TLR- and NLR-dependent mechanisms. This review article will summarize current knowledge about how air pollutants modify TLR- and NLR-dependent signaling and host defense responses in the lung.     

The microbiome and cytosolic innate immune receptors

The discovery of innate immune sensors (pattern recognition receptors, PRRs) has profoundly transformed the notion of innate immunity, in providing a mechanistic basis for host immune interactions with a wealth of environmental signals, leading to a variety of immune-mediated outcomes including instruction and activation of the adaptive immune arm. As part of this growing understanding of host-environmental cross talk, an intimate connection has been unveiled between innate immune sensors and signals perceived from the commensal microbiota, which may be regarded as a hub integrating a variety of environmental cues. Among cytosolic PRRs impacting on host homeostasis by interacting with the commensal microbiota are nucleotide-binding domain, leucine-rich repeat-containing protein receptors (NLRs), together with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)–like receptors (ALRs). NLR sensors have been a particular focus of research, and some NLRs have emerged as key orchestrators of inflammatory responses and host homeostasis. Some NLRs achieve this through the formation of cytoplasmic multiprotein complexes termed inflammasomes. More recently discovered PRRs include retinoic acid-inducible gene-I (RIG-I)–like receptors (RLRs), cyclic GMP-AMP synthase (cGAS), and STING. In the present review, they summarize recent advancements in knowledge on structure and function of cytosolic PRRs and their roles in host-microbiota cross talk and immune surveillance. In addition, we discuss their relevance for human health and disease and future therapeutic applications involving modulation of their activation and signaling.     

Toll样受体2和4在髋关节滑膜巨噬细胞中的表达

目的　探讨TLR2和TLR4在髋关节滑膜巨噬细胞中的表达。 方法　收集2007年至　2010年因髋关节疾病在我院行髋关节手术患者的髋关节滑膜标本共47例,其中股骨颈骨折24例（A组）,股骨头坏死18例（B组）,人工髋关节置换术后假体无菌性松动5例（C组）。采用免疫组化SP法检测TLR2和TLR4在3组的髋关节滑膜巨噬细胞中的表达,在高倍镜（×400）视野下对阳性的巨噬细胞的进行观察及计数,并作统计分析。 结果　各组用histoscore计算阳性巨噬细胞百分数得分,每高倍视野下A组中TLR2（0.27±0.33）,TLR4 （0.69±0.18）;B组中TLR2 （0.31±0.19）,TLR4 （0.71±0.31）;C组中　TLR2 （1.78±0.18）,TLR4 （2.00±0.39）。TLR2和TLR4在C组中表达较A组、B组高（P＜0.001）,而且3组中TLR4均较TLR2表达要高（P＜0.001）。 结论　TLR2及TLR4在人工关节无菌性松动患者的假体周围组织巨噬细胞中表达明显增多,可能参与了巨噬细胞介导的假体无菌性松动过程。