Innate signaling in the inflammatory immune disorders

Pattern recognition receptors (PRRs) of innate immune cells recognize the conserved molecular signatures on pathogens, termed pathogen-associated molecular patterns. PRRs also recognize endogenous damage-associated molecular patterns. Following pathogen infection or tissue damage, the stimulation of PRRs activates distinct but shared signaling pathways that lead to effector mechanisms in innate host defense. PRR signaling is strictly and finely tuned to ensure the appropriate duration and strength to prevent damaging inflammation to the host. Here we attempt to provide a brief background on the agonists and signal transduction pathways of PRRs and summarize the mechanisms underlying the control of PRR signaling, with a particular focus on the recent progress of the involvement of PRR signaling in the inflammatory immune disorders.     

Emerging Principles Governing Signal Transduction by Pattern-Recognition Receptors

The problem of recognizing and disposing of non-self-organisms, whether for nutrients or defense, predates the evolution of multicellularity. Accordingly, the function of the innate immune system is often intimately associated with fundamental aspects of cell biology. Here, we review our current understanding of the links between cell biology and pattern-recognition receptors of the innate immune system. We highlight the importance of receptor localization for the detection of microbes and for the initiation of antimicrobial signaling pathways. We discuss examples that illustrate how pattern-recognition receptors influence, and are influenced by, the general membrane trafficking machinery of mammalian cells. In the future, cell biological analysis likely will rival pure genetic analysis as a tool to uncover fundamental principles that govern host–microbe interactions.The innate immune system uses families of pattern-recognition receptors (PRRs) to recognize diverse microbial ligands (Janeway 1989; Janeway and Medzhitov 2002). During infection, these receptors provide signals that up-regulate general antimicrobial features of the innate immune system as well as instruct and initiate adaptive immunity (Iwasaki and Medzhitov 2010). A significant challenge faced by innate immune recognition is the reliable detection of highly diverse, rapidly evolving microbial organisms, many of which possess virulence mechanisms that enable survival within distinct host niches. Moreover, recognition must be linked to induction of contextual signals appropriate for the type of infection. The specificity, signal transduction, and cell biology of PRRs have evolved under these selective pressures to enable broad recognition of microbes within each host niche.Although the collection of PRRs is decidedly less diverse than antigen receptors of the adaptive immune system, the list of players has grown considerably over the past decade (Kawai and Akira 2010). If one classifies these receptors based on common structure and functional domains, then six families emerge: Toll-like receptors (TLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), AIM-like receptors (ALRs), Nod-like receptors (NLRs), and OAS-like receptors (OLRs) (Geijtenbeek and Gringhuis 2009; Kawai and Akira 2010; Rathinam and Fitzgerald 2011; Lamkanfi and Dixit 2012; Kranzusch et al. 2013). Collectively, these receptors bind a diverse array of targets, including lipoproteins, polysaccharides, nucleic acids, carbohydrate structures, and a few highly conserved microbial proteins. These ligands are typically shared across large microbial classes, which facilitate broad recognition with such a limited number of PRRs. Moreover, alteration or masking of these ligands to avoid PRR activation often results in reduced microbial fitness.The molecular recognition challenge faced by PRRs is all the more complex when one considers the need to detect microbes within distinct subcellular niches. Microbes can be extracellular or intracellular within membrane-bound organelles, within the cytosol, or in the nucleus. In addition, both the innate and adaptive immune mechanisms appropriate for eliminating microbes within these distinct environments are quite distinct, so it is vital that PRR signaling communicate the location of a microbe as well its nature. We now understand that members of the PRR families highlighted above localize to distinct subcellular compartments, and, in some cases, localization can change in a dynamic fashion that regulates or influences recognition and signaling. Moreover, in some cases, signal transduction and resulting gene induction can be dramatically influenced by the organelle from which signaling initiates. Thus, the innate immune system has harnessed the organization inherent to cells as a means of achieving regulation and signaling specificity. Activation of PRRs can also feed back on basic cell biological processes, such as phagocytosis and autophagy, to enhance or accelerate the response to microbial infection.In the following sections, we discuss these links between cell biology and PRRs of mammalian innate immunity. Our discussions of PRR function and signal transduction will be limited to this theme, as a result, in part, of space constraints but also because in-depth reviews of each PRR family have appeared elsewhere. For discussion purposes, we have grouped the transmembrane PRRs together and the cytosolic PRRs together.     

Toll样受体（TLR）介导的天然免疫间的相互调节

模式识别受体（PRR）在宿主细胞识别与抵御微生物病原体中起到了重要作用。Toll样受体（TLR）是研究比较清楚的一类PRR,可以识别多种病原体成份,启动天然免疫反应。此外,近来发现了几类其他模式识别受体,如C型凝集素受体（CLR）,核苷酸寡聚结合域（NOD）样受体（NLR）和视黄酸诱导基因I（RIG—I）样受体（RLR）,表明机体的天然免疫反应受到多种机制的精密调控。本文着重综述TLR与其他PRR在识别病原体和介导天然免疫信号通路间的相互关系。     

抗病毒感染固有免疫应答的信号转导

入侵病毒的探知和适应性免疫应答启动均依靠固有免疫系统。三种模式识别受体(PRRs)在宿主防御系统第一线占据极其重要地位:Toll样受体、维甲酸诱导基因I样受体、核苷酸结合寡聚化结构域样受体。PRRs识别病原相关分子模式(PAMP)或危险信号分子模式(DAMPs)启动和调节固有免疫和适应性免疫应答。每种PRR都有单独的识别配体和细胞定位。激活的PRRs将信号分子传递给其配体分子(MyD88,TRIF,IRAK,IPS-1),配体活化后作为信使激活信号途径下游激酶(IKK复合物,MAPKs,TBK1,RIP-1)和转录因子(NF-κB,AP-1,IRF3),最终产生细胞因子、趋化因子、促炎细胞因子和I型干扰素。本文重点讨论PRRs信号通路及该领域取得的成果,以期为人类健康和免疫疾病防治提供策略。     

Innate immunity and cardiomyocytes in ischemic heart disease

Myocardial ischemia/reperfusion (I/R) is the most common cause of myocardial inflammation, which is primarily a manifestation of the innate immune responses. Innate immunity is activated when pattern recognition receptors (PRRs) respond to molecular patterns common to microbes and to danger signals expressed by injured or infected cells, so called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The expression of various PRRs in cardiomyocytes and the release of DAMPs from cardiomyocytes subjected to I/R injury, through active mechanisms as well as passive processes, enable cardiomyocytes to generate innate immune responses. Studies in isolated heart and cardiomyocytes have confirmed the inflammatory and functional effects of cardiac PRRs especially Toll-like receptors in response to I/R-derived DAMPs, such as heat shock proteins. This review addresses the active role of cardiomyocytes in mediating innate inflammatory responses to myocardial I/R. We propose that cardiomyocytes act as innate immune cells in myocardial I/R injury.     

Recognition of Streptococcus pneumoniae by the innate immune system

Streptococcus pneumoniae is both a frequent colonizer of the upper respiratory tract and a leading cause of life-threatening infections such as pneumonia, meningitis and sepsis. The innate immune system is critical for the control of colonization and for defence during invasive disease. Initially, pneumococci are recognized by different sensors of the innate immune system called pattern recognition receptors (PRRs), which control most subsequent host defence pathways. These PRRs include the transmembrane Toll-like receptors (TLRs) as well as the cytosolic NOD-like receptors (NLRs) and DNA sensors. Recognition of S. pneumoniae by members of these PRR families regulates the production of inflammatory mediators that orchestrate the following immune response of infected as well as neighbouring non-infected cells, stimulates the recruitment of immune cells such as neutrophils and macrophages, and shapes the adaptive immunity. This review summarizes the current knowledge of the function of different PRRs in S. pneumoniae infection.     

Pattern-recognition receptor signaling initiated from extracellular, membrane, and cytoplasmic space

Invading pathogens are recognized by diverse germline-encoded pattern-recognition receptors (PRRs) which are distributed in three different cellular compartments: extracellular, membrane, and cytoplasmic. In mammals, the major extracellular PRRs such as complements may first encounter the invading pathogens and opsonize them for clearance by phagocytosis which is mediated by membrane-associated phagocytic receptors including complement receptors. The major membrane-associated PRRs, Toll-like receptors, recognize diverse pathogens and generate inflammatory signals to coordinate innate immune responses and shape adaptive immune responses. Furthemore, certain membrane-associated PRRs such as Dectin-1 can mediate phagocytosis and also induce inflammatory response. When these more forefront detection systems are avoided by the pathogens, cytoplasmic PRRs may play major roles. Cytoplasmic caspase-recruiting domain (CARD) helicases such as retinoic acid-inducible protein I (RIG-I)melanoma differentiation-associated gene 5 (MDA5), mediate antiviral immunity by inducing the production of type I interferons. Certain members of nucleotide-binding oligomerization domain (NOD)-like receptors such as NALP3 present in the cytosol form inflammasomes to induce inflammatory responses upon ligand recognition. Thus, diverse families of PRRs coordinately mediate immune responses against diverse types of pathogens.     

Molecular view on PRR cross-talk in antifungal immunity

The identification of a major class of innate immune receptors, termed pattern recognition receptors (PRRs), has boosted research on innate pathogen recognition. The immune response to a specific pathogen is not restricted to the recognition by one type of PRR or activation of a single cell type, but instead comprises complex collaborations between different receptors, cells and signal mediators. Here we will discuss the cross-talk between PRRs involved in fungal recognition, focusing on the molecular interactions occurring at the plasma membrane.     

Plant and animal pathogen recognition receptors signal through non-RD kinases

Plants and animals mediate early steps of the innate immune response through pathogen recognition receptors (PRRs). PRRs commonly associate with or contain members of a monophyletic group of kinases called the interleukin-1 receptor-associated kinase (IRAK) family that include Drosophila Pelle, human IRAKs, rice XA21 and Arabidopsis FLS2. In mammals, PRRs can also associate with members of the receptor-interacting protein (RIP) kinase family, distant relatives to the IRAK family. Some IRAK and RIP family kinases fall into a small functional class of kinases termed non-RD, many of which do not autophosphorylate the activation loop. We surveyed the yeast, fly, worm, human, Arabidopsis, and rice kinomes (3,723 kinases) and found that despite the small number of non-RD kinases in these genomes (9%-29%), 12 of 15 kinases known or predicted to function in PRR signaling fall into the non-RD class. These data indicate that kinases associated with PRRs can largely be predicted by the lack of a single conserved residue and reveal new potential plant PRR subfamilies.     

Characterisation of innate fungal recognition in the lung

The innate recognition of fungi by leukocytes is mediated by pattern recognition receptors (PRR), such as Dectin-1, and is thought to occur at the cell surface triggering intracellular signalling cascades which lead to the induction of protective host responses. In the lung, this recognition is aided by surfactant which also serves to maintain the balance between inflammation and pulmonary function, although the underlying mechanisms are unknown. Here we have explored pulmonary innate recognition of a variety of fungal particles, including zymosan, Candida albicans and Aspergillus fumigatus, and demonstrate that opsonisation with surfactant components can limit inflammation by reducing host-cell fungal interactions. However, we found that this opsonisation does not contribute directly to innate fungal recognition and that this process is mediated through non-opsonic PRRs, including Dectin-1. Moreover, we found that pulmonary inflammatory responses to resting Aspergillus conidia were initiated by these PRRs in acidified phagolysosomes, following the uptake of fungal particles by leukocytes. Our data therefore provides crucial new insights into the mechanisms by which surfactant can maintain pulmonary function in the face of microbial challenge, and defines the phagolysosome as a novel intracellular compartment involved in the innate sensing of extracellular pathogens in the lung.     

Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses

Antigen presenting cells recognize pathogens via pattern recognition receptors (PRR), which upon ligation transduce intracellular signals that can induce innate immune responses. Because some C-type lectin-like receptors (e.g. dectin-1 and DCSIGN) were shown to act as PRR for particular microbes, we considered a similar role for dectin-2. Binding assays using soluble dectin-2 receptors showed the extracellular domain to bind preferentially to hyphal (rather than yeast/conidial) components of Candida albicans, Microsporum audouinii, and Trichophyton rubrum. Selective binding for hyphae was also observed using RAW macrophages expressing dectin-2, the ligation of which by hyphae or cross-linking with dectin-2-specific antibody led to protein tyrosine phosphorylation. Because dectin-2 lacks an intracellular signaling motif, we searched for a signal adaptor that permits it to transduce intracellular signals. First, we found that the Fc receptor gamma (FcRgamma) chain can bind to dectin-2. Second, ligation of dectin-2 on RAW cells induced tyrosine phosphorylation of FcRgamma, activation of NF-kappaB, internalization of a surrogate ligand, and up-regulated secretion of tumor necrosis factor alpha and interleukin-1 receptor antagonist. Finally, these dectin-2-induced events were blocked by PP2, an inhibitor of Src kinases that are mediators for FcRgamma chain-dependent signaling. We conclude that dectin-2 is a PRR for fungi that employs signaling through FcRgamma to induce innate immune responses.     

Advances in Nod-like receptors (NLR) biology

The innate immune system is composed of a wide repertoire of conserved pattern recognition receptors (PRRs) able to trigger inflammation and host defense mechanisms in response to endogenous or exogenous pathogenic insults. Among these, nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are intracellular sentinels of cytosolic sanctity capable of orchestrating innate immunity and inflammatory responses following the perception of noxious signals within the cell. In this review, we elaborate on recent advances in the signaling mechanisms of NLRs, operating within inflammasomes or through alternative inflammatory pathways, and discuss the spectrum of their effector functions in innate immunity. We describe the progressive characterization of each NLR with associated controversies and cutting edge discoveries.     

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.     

PRRs in pathogen recognition

The innate immune system provides the first line of host defense against invading microorganisms before the development of adaptive immune responses. Innate immune responses are initiated by germline-encoded pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Toll-like receptors (TLRs) are pattern-recognition receptors that sense a wide range of microorganisms, including bacteria, fungi, protozoa and viruses. TLRs exist either on the cell surface or in the lysosome/endosome compartment and induce innate immune responses. Recently, cytoplasmic PRRs have been identified which detect pathogens that have invaded the cytosol. This review focuses on the pathogen recognition of PRRs in innate immunity.     

Role of Nods in bacterial infection

Research into intracellular sensing of microbial products is an up and coming field in innate immunity. Nod1 and Nod2 are members of the rapidly expanding family of NACHT domain-containing proteins involved in intracellular recognition of bacterial products. Nods proteins are involved in the cytosolic detection of peptidoglycan motifs of bacteria, recognized through the LRR domain. The role of the NACHT-LRR system of detection in innate immune responses is highlighted at the mucosal barrier, where most of the membranous Toll like receptors (TLRs) are not expressed, or with pathogens that have devised ways to escape TLR sensing. For a given pathogen, the sum of the pathways induced by the recognition of the different "pathogen associated molecular patterns" (PAMPs) by the different pattern recognition receptors (PRRs) trigger and shape the subsequent innate and adaptive immune responses. Knowledge gathered during the last decade on PRR and their agonists, and recent studies on bacterial infections provide new insights into the immune response and the pathogenesis of human infectious diseases.     

鱼类模式识别受体的研究进展

天然免疫（innate immunity）是基于对病原微生物成分的非克隆性识别而启动的快速防御反应。天然免疫系统可通过胚系编码的模式识别受体（pattern-recognition receptors,PRR）识别恒定不变的病原基元,即病原相关分子模式（pathogen-associated molecular patterns,PAMPs）,启动信号级联转导,最终PRRs信号激活宿主免疫和前炎性基因的表达,引发针对所识别病原的免疫反应。目前PRRs主要分为5类,即C-型Lectins、Toll样受体（Toll-like receptors,TLRs）、视黄酸诱导基因I样受体（retinoic acid inducible gene I-like receptors,RLRs）、包含核苷酸结合区和亮氨酸富集区蛋白（the nucleotide-binding domain,leucine-rich repeatcontaining proteins,NLRs,也称NOD样受体）和最近发现的AIM样受体（absent in melanoma（AIM）-like receptors,ALRs）。近年来,随着5种鱼类基因组序列草图的完成,大量鱼类PRRs基因被发现,一些PRRs的配体特异性及其相关信号途径正在逐渐明晰。为此,将对鱼类Toll样受体（TLRs）、视黄酸诱导基因I样受体（RLRs）和NOD样受体（NLRs）的研究进展进行综述。     

革兰阴性菌结合蛋白(Toll/GNBPs)和肽聚糖识别蛋白(PGRPs)在无脊椎动物先天免疫应答中的作用

由于无脊椎动物没有专一的特异性免疫系统,所以先天免疫系统是其抵御外来病原入侵的唯一方式,无脊椎动物的先天免疫系统包括细胞和体液防卫机制,这2种机制可被模式识别受体(PRR s)分子所触发,PRR s可与微生物表面特异的物质识别并结合,通过结合,这些PRR s通过包囊和噬菌作用直接杀死微生物,或者通过丝氨酸蛋白酶级联反应和细胞内免疫信号途径间接引发不同的防御反应以抵御病原微生物。革兰阴性菌结合蛋白(GNBPs)和肽聚糖识别蛋白(PGRPs)作为无脊椎动物先天免疫系统中的一类重要模式识别受体,在识别微生物病原并引发一系列级联反应做出免疫应答过程中起重要作用。本文主要对GNBPs和PGRPs在无脊椎动物中的研究进展及其在先天免疫应答过程中的作用机制进行综述。     

The Adjuvant Activity of Alphavirus Replicons Is Enhanced by Incorporating the Microbial Molecule Flagellin into the Replicon

Ligands of pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) stimulate innate and adaptive immune responses and are considered as potent adjuvants. Combinations of ligands might act in synergy to induce stronger and broader immune responses compared to stand-alone ligands. Alphaviruses stimulate endosomal TLRs 3, 7 and 8 as well as the cytoplasmic PRR MDA-5, resulting in induction of a strong type I interferon (IFN) response. Bacterial flagellin stimulates TLR5 and when delivered intracellularly the cytosolic PRR NLRC4, leading to secretion of proinflammatory cytokines. Both alphaviruses and flagellin have independently been shown to act as adjuvants for antigen-specific antibody responses. Here, we hypothesized that alphavirus and flagellin would act in synergy when combined. We therefore cloned the Salmonella Typhimurium flagellin (FliC) gene into an alphavirus replicon and assessed its adjuvant activity on the antibody response against co-administered antigen. In mice immunized with recombinant alphavirus, antibody responses were greatly enhanced compared to soluble FliC or control alphavirus. Both IgG1 and IgG2a/c responses were increased, indicating an enhancement of both Th1 and Th2 type responses. The adjuvant activity of FliC-expressing alphavirus was diminished but not abolished in the absence of TLR5 or type I IFN signaling, suggesting the contribution of several signaling pathways and some synergistic and redundant activity of its components. Thus, we have created a recombinant adjuvant that stimulates multiple signaling pathways of innate immunity resulting in a strong and broad antibody response.     

From virus to inflammation: mechanisms of RIG-I-induced IL-1β production

Early detection of viruses by the innate immune system is critical for host defense. Antiviral immunity is initiated by germline encoded pattern recognition receptors (PRRs) that recognize viral pathogen-associated molecular patterns (PAMPs) such as nucleic acids. Intracellular PRRs then drive the production of interferons and cytokines to orchestrate immune responses. One key host factor that is critical for antiviral immunity and for systemic inflammatory reactions including fever is interleukin-1beta (IL-1β). Here we discuss current insights into the molecular mechanisms how the cytosolic RNA helicase RIG-I triggers NF-κB signaling and inflammasome activation specifically for RNA virus-induced IL-1β production.     

固有免疫细胞及其模式识别受体与表观遗传学调控研究进展

固有免疫细胞是机体抵御病原微生物的首道防线,亦是机体有效启动和维持免疫反应的重要参与者,而模式识别受体是固有免疫细胞发挥免疫功能的重要免疫分子,因此,机体对固有免疫细胞及其模式识别受体的精细调控尤为重要。表观遗传学是近年研究热点,其在固有免疫调节中的作用逐渐受到重视。就近年表观遗传学中的DNA甲基化、组蛋白共价修饰及非编码RNA等在调节固有免疫细胞分化发育及其模式识别受体的相关研究作一简述,以期为感染、炎症、自身免疫病等研究与防治提供新的思路和策略。