The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

doi:10.1038/NI.1863

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The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Journal Article•DOI•

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Taro Kawai¹, Shizuo Akira¹•Institutions (1)

Osaka University¹

01 May 2010-Nature Immunology (Nature Research)-Vol. 11, Iss: 5, pp 373-384

TL;DR: Recent advances that have been made by research into the role of TLR biology in host defense and disease are described.

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Abstract: The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

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Journal Article•DOI•

NF-κB signaling in inflammation

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Ting Liu¹, Lingyun Zhang¹, Donghyun Joo¹, Shao Cong Sun¹, Shao Cong Sun² - Show less +1 more•Institutions (2)

University of Texas MD Anderson Cancer Center¹, University of Texas at Austin²

14 Jul 2017-Signal Transduction and Targeted Therapy

TL;DR: This review will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-σB inhibition.

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Abstract: The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.

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4,110 citations

Journal Article•DOI•

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status.

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Yan Rong Guo, Qing Dong Cao¹, Zhong Si Hong¹, Yuan Yang Tan, Shoudeng Chen, Hong Jun Jin, Kai Sen Tan², De Yun Wang², Yan Yan¹ - Show less +5 more•Institutions (2)

Sun Yat-sen University¹, National University of Singapore²

13 Mar 2020-Military Medical Research

TL;DR: The latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19 are summarized, and the current treatment and scientific advancements to combat the epidemic novel coronavirus are discussed.

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Abstract: An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.

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3,277 citations

Journal Article•DOI•

Toll-like Receptors and Their Crosstalk with Other Innate Receptors in Infection and Immunity

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Taro Kawai¹, Shizuo Akira¹•Institutions (1)

Osaka University¹

27 May 2011-Immunity

TL;DR: The role played by TLRs in mounting protective immune responses against infection and their crosstalk with other PRRs with respect to pathogen recognition is focused on.

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3,113 citations

Cites background from "The role of pattern-recognition rec..."

...TLR4 is the only TLR that recruits four adaptor proteins and activates two distinct signaling pathways: the ‘‘MyD88-dependent’’ and ‘‘TRIF-dependent’’ pathways (Kawai and Akira, 2010)....
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...MyD88 then recruits IRAKs, TRAF6, and the TAK1 complex, leading to early-phase activation of NF-kB andMAP kinases (Kawai and Akira, 2010)....
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...Upon recognition of respective PAMPs, TLRs recruit a specific set of adaptor molecules that harbor TIR domain, such as MyD88 and TRIF, and initiate downstream signaling events that leads to the secretion of inflammatory cytokines, type I IFN, chemokines, and antimicrobial peptides (Kawai and Akira, 2010)....
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...The specific response initiated by individual TLRs depends on the recruitment of a single, or a specific combination of, TIRdomain-containing adaptor protein (e.g., MyD88, TIRAP, TRIF, or TRAM) (Figure 1; Kawai and Akira, 2010)....
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...…of respective PAMPs, TLRs recruit a specific set of adaptor molecules that harbor TIR domain, such as MyD88 and TRIF, and initiate downstream signaling events that leads to the secretion of inflammatory cytokines, type I IFN, chemokines, and antimicrobial peptides (Kawai and Akira, 2010)....
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Journal Article•DOI•

Toll-like receptor signaling pathways.

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Takumi Kawasaki¹, Taro Kawai¹•Institutions (1)

Nara Institute of Science and Technology¹

25 Sep 2014-Frontiers in Immunology

TL;DR: Recent progress is described in the understanding of TLR signaling regulation and its contributions to host defense.

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Abstract: Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.

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2,398 citations

Journal Article•DOI•

Pathogen Recognition by the Innate Immune System

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Himanshu Kumar, Taro Kawai¹, Shizuo Akira¹•Institutions (1)

Osaka University¹

14 Jan 2011-International Reviews of Immunology

TL;DR: In this review, a comprehensively review the recent progress in the field of PAMP recognition by PRRs and the signaling pathways activated byPRRs.

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Abstract: Microbial infection initiates complex interactions between the pathogen and the host. Pathogens express several signature molecules, known as pathogen-associated molecular patterns (PAMPs), which are essential for survival and pathogenicity. PAMPs are sensed by evolutionarily conserved, germline-encoded host sensors known as pathogen recognition receptors (PRRs). Recognition of PAMPs by PRRs rapidly triggers an array of anti-microbial immune responses through the induction of various inflammatory cytokines, chemokines and type I interferons. These responses also initiate the development of pathogen-specific, long-lasting adaptive immunity through B and T lymphocytes. Several families of PRRs, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), and DNA receptors (cytosolic sensors for DNA), are known to play a crucial role in host defense. In this review, we comprehensively review the recent progress in the field of PAMP recognition by PRRs and the signaling pathways activated by PRRs.

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1,896 citations

Cites background or result from "The role of pattern-recognition rec..."

...The genomic DNA and hematin crystals of Trypanosoma and Plasmodium species, respectively, are sensed by TLR9 [2, 3, 6, 20]....
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...TLR5 and TLR9 sense the flagellin protein expressed by flagellated bacteria and bacterial/viral genomic DNA rich in unmethylated CpG, respectively [6, 20]....
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...Notably, this recognition induces the production of type I interferons by inflammatory monocytes [2, 3, 6, 20]....
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...In cDCs, UNC93B1 (a protein localized to the endoplasmic reticulum (ER)) plays a critical role in the transportation of endosome-localized TLRs, such as TLR3, TLR7, and TLR9....
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...Recognition of PAMPs by TLR1, TLR2, TLR4, TLR5 and TLR6 primarily induces the production of inflammatory cytokines, whereas TLR7 and TLR9 induce type I interferons....
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References

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Journal Article•DOI•

Pathogen Recognition and Innate Immunity

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Shizuo Akira¹, Satoshi Uematsu¹, Osamu Takeuchi¹•Institutions (1)

Osaka University¹

24 Feb 2006-Cell

TL;DR: New insights into innate immunity are changing the way the way the authors think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.

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10,685 citations

"The role of pattern-recognition rec..." refers background in this paper

...These findings suggest that the PI(3)K-mTOR pathway accelerates the production of type I interferon by pDCs during viral infection....
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...Pharmacological inhibition of phosphoinositol 3-OH kinase (PI(3) K) abrogates the nuclear translocation of IRF7....
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...Moreover, inhibition of mTOR and p70S6K, both of which are downstream targets of PI(3) K, disrupts the interaction between TLR9 and MyD88, which results in impaired nuclear translocation of IRF7 and induction of type I interferon68....
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...The PI(3)K-mTOR-p70S6K axis enhances the TLR7 and TLR9 signaling pathways....
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...Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway....
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Journal Article•DOI•

Innate Immune Recognition

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Charles A. Janeway¹, Ruslan Medzhitov¹•Institutions (1)

Yale University¹

01 Jan 2002-Annual Review of Immunology

TL;DR: Microbial recognition by Toll-like receptors helps to direct adaptive immune responses to antigens derived from microbial pathogens to distinguish infectious nonself from noninfectious self.

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Abstract: ▪ Abstract The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses. Stimulation of Toll-like receptors by microbial products leads to the activation of signaling pathways that result in the induction of antimicrobial genes and inflammatory cytokines. In addition, stimulation of Toll-like receptors triggers dendritic cell maturation and results in the induction of costimulatory molecules and increased antigen-presenting capacity. Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses ...

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8,041 citations

"The role of pattern-recognition rec..." refers background in this paper

...The early concept of innate immunity was that it nonspecifically recognized microbes; however, the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs...
[...]

Journal Article•DOI•

Toll-like receptors: critical proteins linking innate and acquired immunity.

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Shizuo Akira¹, Kiyoshi Takeda¹, Tsuneyasu Kaisho¹•Institutions (1)

Osaka University¹

01 Aug 2001-Nature Immunology

TL;DR: Evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.

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Abstract: Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.

...read moreread less

4,686 citations

"The role of pattern-recognition rec..." refers background in this paper

...The early concept of innate immunity was that it nonspecifically recognized microbes; however, the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs...
[...]

Journal Article•DOI•

NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses

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Konstantin Taganov¹, Mark Boldin, Kuang Jung Chang, David Baltimore•Institutions (1)

California Institute of Technology¹

15 Aug 2006-Proceedings of the National Academy of Sciences of the United States of America

TL;DR: A role is proposed for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor- associated factor 6 protein levels.

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Abstract: Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to control their onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processes at the level of posttranscriptional repression. Expression profiling of 200 microRNAs in human monocytes revealed that several of them (miR-146a/b, miR-132, and miR-155) are endotoxin-responsive genes. Analysis of miR-146a and miR-146b gene expression unveiled a pattern of induction in response to a variety of microbial components and proinflammatory cytokines. By means of promoter analysis, miR-146a was found to be a NF-κB-dependent gene. Importantly, miR-146a/b were predicted to base-pair with sequences in the 3′ UTRs of the TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 genes, and we found that these UTRs inhibit expression of a linked reporter gene. These genes encode two key adapter molecules downstream of Toll-like and cytokine receptors. Thus, we propose a role for miR-146 in control of Toll-like receptor and cytokine signaling through a negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor-associated factor 6 protein levels.

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3,947 citations

Journal Article•DOI•

The Inflammasomes: Guardians of the Body

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Fabio Martinon¹, Annick Mayor, Jiirg Tschopp²•Institutions (2)

Harvard University¹, University of Lausanne²

20 Mar 2009-Annual Review of Immunology

TL;DR: The role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease are discussed.

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Abstract: The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1β and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.

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2,217 citations

"The role of pattern-recognition rec..." refers background in this paper

...The NLR family consists of more than 20 members, and several respond to the various PAMPs, non-PAMP particles and cellular stresses to trigger proinflammatory responses, including the secretion of IL-1&beta...
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