Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity

Host cells trigger signals for innate immune responses upon recognition of conserved structures in microbial pathogens. Nucleic acids, which are critical components for inheriting genetic information in all species including pathogens, are key structures sensed by the innate immune system. The corresponding receptors for foreign nucleic acids include members of Toll-like receptors, RIG-I-like receptors, and intracellular DNA sensors. While nucleic acid recognition by these receptors is required for host defense against the pathogen, there is a potential risk to the host of self-nucleic acids recognition, thus precipitating autoimmune and autoinflammatory diseases. In this review, we discuss the roles of nucleic acid-sensing receptors in guarding against pathogen invasion, discriminating between self and non-self, and contributing to autoimmunity and autoinflammatory diseases.     

Nucleic acid sensing Toll-like receptors in dendritic cells

Dendritic cells (DCs) are crucial immune cells detecting microorganisms and linking innate and adaptive immunity. Various microorganism-derived components, including lipids, proteins, or nucleic acids, activate DCs through various pattern recognition receptors (PRRs). PRRs can principally detect non-self-components, but nucleic acid components are peculiar in that self-derived nucleic acids can also stimulate PRRs. Thus, nucleic-acid-sensing PRRs can potentially cause autoimmune responses. This potential danger comes out in certain situations, and especially nucleic-acid-induced type I interferon production contributes to the pathogenesis of autoimmune disorders. Here we review how DCs detect and respond to nucleic acid adjuvants and how self-derived nucleic acids can cause autoimmunity. Clarifying such mechanisms should contribute to the development of therapeutic manipulation for autoimmune diseases.     

Nuclear innate sensors for nucleic acids in immunity and inflammation

Innate sensors recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) to initiate innate immune response by activating downstream signaling. These evolutionarily conserved innate sensors usually locate in the plasma membrane or cytoplasm. However, the nucleus-localized innate sensors are recently found to detect pathogenic nucleic acids for initiating innate response, demonstrating a complicated crosstalk with cytoplasmic sensors and signaling molecules to form an elaborate tiered innate signaling network between nucleus and cytoplasm. Furthermore, these nuclear innate sensors evolve varied mechanisms for discriminating self from non-self nucleic acids to maintain immune homeostasis and avoid autoinflammatory immune response. In this review, we summarize the recent findings on the identification of nuclear innate sensors for nucleic acids, such as hnRNPA2B1, IFI16, SAFA, and their roles in host defense and inflammatory response.     

Intracellular nucleic acid sensors and autoimmunity

A collection of molecular sensors has been defined by studies in the last decade that can recognize a diverse array of pathogens and initiate protective immune and inflammatory responses. However, if the molecular signatures recognized are shared by both foreign and self-molecules, as is the case of nucleic acids, then the responses initiated by these sensors may have deleterious consequences. Notably, this adverse occurrence may be of primary importance in autoimmune disease pathogenesis. In this case, microbe-induced damage or mishandled physiologic processes could lead to the generation of microparticles containing self-nucleic acids. These particles may inappropriately gain access to the cytosol or endolysosomes and, hence, engage resident RNA and DNA sensors. Evidence, as reviewed here, strongly indicates that these sensors are primary contributors to autoimmune disease pathogenesis, spearheading efforts toward development of novel therapeutics for these disorders.     

Innate immune recognition of viral infection

Induction of the antiviral innate immune response depends on recognition of viral components by host pattern-recognition receptors. Members of the Toll-like receptor family have emerged as key sensors that recognize viral components such as nucleic acids. Toll-like receptor signaling results in the production of type I interferon and inflammatory cytokines and leads to dendritic cell maturation and establishment of antiviral immunity. Cells also express cytoplasmic RNA helicases that function as alternative pattern-recognition receptors through recognition of double-stranded RNA produced during virus replication. These two classes of pattern-recognition receptor molecules are expressed in different intracellular compartments and induce type I interferon responses via distinct signaling pathways.     

Recognition of viral nucleic acids in innate immunity

Viral infections are detected by sensor molecules, which initiate innate antiviral responses, including the activation of type I interferons (IFNs) and proinflammatory cytokines. These cytokines are responsible for not only inhibiting viral replication in infected cells but also regulating the induction of adaptive immunity, leading to the swift eradication of viruses. Recent advances in the identification of pathogen receptors in the innate immune system have revealed that distinct types of sensors play a role in the detection of viral nucleic acids in different ways; Toll‐like receptors (TLRs), which detect viral DNA or RNA in endosomal compartments in immune cells, retinoic acid inducible gene‐I (RIG‐I)‐like receptors (RLRs), which recognise viral RNA in the cytoplasm, and DNA sensors, which detect cytoplasmic viral DNA. Since these sensors have to exclusively recognise viral infections, it is intriguing to understand how they distinguish self nucleic acids from foreign viral ones. Here, we review the current knowledge of the recognition of viral nucleic acids by these sensor molecules and the signal transduction machinery. Copyright © 2009 John Wiley & Sons, Ltd.     

Toll like receptors and autoimmunity: a critical appraisal

There is a constant interplay between the innate and adaptive immune systems, which leads to a protective immune response against pathogens and contributes effectively to self-non-self discrimination. Toll-like receptors (TLRs) are key components of the innate immune system, which activate multiple inflammatory pathways and coordinate systemic defense against pathogens. In addition to recognizing unique molecular patterns associated with different classes of pathogens, TLRs may also recognize a number of self proteins and endogenous nucleic acids. Data originating predominantly from animal models of autoimmune disease and circumstantial data from human patients suggest that inappropriate activation of TLR pathways by endogenous or exogenous ligands may lead to the initiation and/or perpetuation of autoimmune responses and tissue injury.     

Pattern recognition of viral nucleic acids by RIG-I-like helicases

Recognition of pathogenic microbes by the innate immune system is based on the principle of pathogen-associated molecular patterns (PAMPs). These are conserved molecular structures that are present in the pathogen but not in the host. Cells of the innate immune system or, in some cases, virtually all cells of our body express receptors that are able to specifically recognize PAMPs and trigger the appropriate responses including the production of cytokines. In the case of viruses, an interesting complication exists: Viruses use the host’s cellular metabolism and building blocks to replicate. As a consequence, protein modifications, lipid or carbohydrate configurations restricted to viruses do not exist. Instead, parts of the innate immune system have evolved to detect viral nucleic acids mainly by virtue of their (non-physiological) localization and structure. Understanding the molecules involved in anti-viral defence and the patterns they recognize will allow harnessing them for therapeutic strategies targeting viral and autoimmune diseases and tumours. This review presents important recent advances in understanding intracellular recognition of nucleic acid patterns by the innate immune system.     

Camouflage and interception: how pathogens evade detection by intracellular nucleic acid sensors

Intracellular DNA and RNA sensors play a vital part in the innate immune response to viruses and other intracellular pathogens, causing the secretion of type I interferons, cytokines and chemokines from infected cells. Pathogen RNA can be detected by retinoic-acid inducible gene I-like receptors in the cytosol, whereas cytosolic DNA is recognized by DNA sensors such as cyclic GMP-AMP synthase (cGAS). The resulting local immune response, which is initiated within hours of infection, is able to eliminate many pathogens before they are able to establish an infection in the host. For this reason, all viruses, and some intracellular bacteria and protozoa, need to evade detection by nucleic acid sensors. Immune evasion strategies include the sequestration and modification of nucleic acids, and the inhibition or degradation of host factors involved in innate immune signalling. Large DNA viruses, such as herpesviruses, often use multiple viral proteins to inhibit signalling cascades at several different points; for instance herpes simplex virus 1 targets both DNA sensors cGAS and interferon-γ-inducible protein 16, as well as the adaptor protein STING (stimulator of interferon genes) and other signalling factors in the pathway. Viruses with a small genome encode only a few immunomodulatory proteins, but these are often multifunctional, such as the NS1 protein from influenza A virus, which inhibits RNA sensing in multiple ways. Intracellular bacteria and protozoa can also be detected by nucleic acid sensors. However, as the type I interferon response is not always beneficial for the host under these circumstances, some bacteria subvert, rather than evade, these signalling cascades for their own gain.     

Impact of intracellular innate immune receptors on immunometabolism

Immunometabolism, which is the metabolic reprogramming of anaerobic glycolysis, oxidative phosphorylation, and metabolite synthesis upon immune cell activation, has gained importance as a regulator of the homeostasis, activation, proliferation, and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity. Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection, inflammation, cancer, autoimmune diseases, and metabolic disorders. The crosstalk between the PI3K–AKT–mTOR and LKB1–AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism. The bidirectional interaction between immune cells and metabolism is a topic of intense study. Toll-like receptors (TLRs), cytokine receptors, and T and B cell receptors have been shown to activate multiple downstream metabolic pathways. However, how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood. The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors, such as nucleotide-binding and leucine-rich repeat-containing receptors (NLRs, or NOD-like receptors), absent in melanoma 2 (AIM2)-like receptors (ALRs), and the cyclic dinucleotide receptor stimulator of interferon genes (STING). We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways. Whenever appropriate, this review will provide a brief contextual connection to pathogenic infections, autoimmune diseases, cancers, metabolic disorders, and/or inflammatory bowel diseases.     

Mouse models for Aicardi–Goutières syndrome provide clues to the molecular pathogenesis of systemic autoimmunity

Aicardi–Goutières syndrome (AGS) is a hereditary autoimmune disease which overlaps clinically and pathogenetically with systemic lupus erythematosus (SLE), and can be regarded as a monogenic variant of SLE. Both conditions are characterized by chronic activation of anti‐viral type I interferon (IFN) responses. AGS can be caused by mutations in one of several genes encoding intracellular enzymes all involved in nucleic acid metabolism. Mouse models of AGS‐associated defects yielded distinct phenotypes and reproduced important features of the disease. Analysis of these mutant mouse lines stimulated a new concept of autoimmunity caused by intracellular accumulations of nucleic acids, which trigger a chronic cell‐intrinsic antiviral type I IFN response and thereby autoimmunity. This model is of major relevance for our understanding of SLE pathogenesis. Findings in gene‐targeted mice deficient for AGS associated enzymes are summarized in this review.     

核酸传感器与CD72在系统性红斑狼疮中的作用

系统性红斑狼疮（SLE）是一种多发于青年女性的累及多个脏器的自身免疫性炎症性结缔组织疾病,其特征为机体产生针对各种细胞核抗原的自身抗体。核酸（NA）传感器在这一过程中起关键作用,一方面NA传感器可以识别微生物NA,并诱导抗微生物的免疫反应;另一方面也可以识别自身NA使B细胞产生自身抗体,同时使类浆细胞的树突状细胞产生IFN-I。CD72是一种抑制性的B细胞共受体,已有研究显示CD72可以调控SLE的发生发展。本文针对核酸传感器与CD72在系统性红斑狼疮中的作用作一简要综述,旨在为临床治疗提供参考。     

Interferons in autoimmune and inflammatory diseases: regulation and roles

Several lines of evidence strongly implicate type I interferons (IFN-α and β) and IFN-signaling in the pathogenesis of certain autoimmune inflammatory diseases. Accordingly, genome-wide association studies have identified polymorphisms in the type I IFN-signaling pathways. Other studies also indicate that a feed-forward loop of type I IFN production, which involves sensing of cytoplasmic nucleic acids by sensors, contributes to the development of immunopathology. In addition, a mutually positive regulatory feedback loop between type I IFNs and estrogen receptor-α may contribute to a gender bias, thus resulting in an increased production of type I IFNs and associated immunopathology in women. Increased levels of type I IFNs have numerous immunomodulatory functions for both the innate and adaptive immune responses. Given that the IFN-β also has some anti-inflammatory roles, identifying molecular links among certain genotypes, cytokine profiles, and associated phenotypes in patients with autoimmune inflammatory diseases is likely to improve our understanding of autoimmunity-associated pathogenesis and suboptimal outcomes following standard therapies.     

Exosomes carrying immunoinhibitory proteins and their role in cancer

Recent emergence of exosomes as information carriers between cells has introduced us to a new previously unknown biological communication system. Multi‐directional cross‐talk mediated by exosomes carrying proteins, lipids and nucleic acids between normal cells, cells harbouring a pathogen or cancer and immune cells has been instrumental in determining outcomes of physiological as well as pathological conditions. Exosomes play a key role in the broad spectrum of human diseases. In cancer, tumour‐derived exosomes carry multiple immunoinhibitory signals, disable anti‐tumour immune effector cells and promote tumour escape from immune control. Exosomes delivering negative signals to immune cells in cancer, viral infections, autoimmune or other diseases may interfere with therapy and influence outcome. Exosomes can activate tissue cells to produce inhibitory factors and thus can suppress the host immune responses indirectly. Exosomes also promise to be non‐invasive disease biomarkers with a dual capability to provide insights into immune dysfunction as well as disease progression and outcome.     

Innate recognition of viruses

Virus infection elicits potent responses in all cells intended to contain virus spread before intervention by the adaptive immune system. Central to this process is the virus-elicited production of type I interferons (IFNs) and other cytokines. The sensors involved in coupling recognition of viruses to the induction of the type I IFN genes have only recently been uncovered and include endosomal and cytosolic receptors for RNA and DNA. Here, we review their properties and discuss how their ability to recognize the unusual presence of atypical nucleic acids in particular subcellular compartments is used by the body to detect virus presence.     

Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus

Double‐stranded (ds) DNA, DNA‐ or RNA‐associated nucleoproteins are the primary autoimmune targets in SLE, yet their relative inability to trigger similar autoimmune responses in experimental animals has fascinated scientists for decades. While many cellular proteins bind non‐specifically negatively charged nucleic acids, it was discovered only recently that several intracellular proteins are involved directly in innate recognition of exogenous DNA or RNA, or cytosol‐residing DNA or RNA viruses. Thus, endosomal Toll‐like receptors (TLR) mediate responses to double‐stranded RNA (TLR‐3), single‐stranded RNA (TLR‐7/8) or unmethylated bacterial cytosine (phosphodiester) guanine (CpG)‐DNA (TLR‐9), while DNA‐dependent activator of IRFs/Z‐DNA binding protein 1 (DAI/ZBP1), haematopoietic IFN‐inducible nuclear protein‐200 (p202), absent in melanoma 2 (AIM2), RNA polymerase III, retinoic acid‐inducible gene‐I (RIG‐I) and melanoma differentiation‐associated gene 5 (MDA5) mediate responses to cytosolic dsDNA or dsRNA, respectively. TLR‐induced responses are more robust than those induced by cytosolic DNA‐ or RNA‐ sensors, the later usually being limited to interferon regulatory factor 3 (IRF3)‐dependent type I interferon (IFN) induction and nuclear factor (NF)‐κB activation. Interestingly, AIM2 is not capable of inducing type I IFN, but rather plays a role in caspase I activation. DNA‐ or RNA‐like synthetic inhibitory oligonucleotides (INH‐ODN) have been developed that antagonize TLR‐7‐ and/or TLR‐9‐induced activation in autoimmune B cells and in type I IFN‐producing dendritic cells at low nanomolar concentrations. It is not known whether these INH‐ODNs have any agonistic or antagonistic effects on cytosolic DNA or RNA sensors. While this remains to be determined in the future, in vivo studies have already shown their potential for preventing spontaneous lupus in various animal models of lupus. Several groups are exploring the possibility of translating these INH‐ODNs into human therapeutics for treating SLE and bacterial DNA‐induced sepsis.     

Peptidoglycan: a critical activator of the mammalian immune system during infection and homeostasis

Peptidoglycan is a conserved structural component of the bacterial cell wall with molecular motifs unique to bacteria. The mammalian immune system takes advantage of these properties and has evolved to recognize this microbial associated molecular pattern. Mammals have four secreted peptidoglycan recognition proteins, PGLYRP-1-4, as well as two intracellular sensors of peptidoglycan, Nod1 and Nod2. Recognition of peptidoglycan is important in initiating and shaping the immune response under both homeostatic and infection conditions. During infection, peptidoglycan recognition drives both cell-autonomous and whole-organism defense responses. Here, we examine recent advances in the understanding of how peptidoglycan recognition shapes mammalian immune responses in these diverse contexts.     

Genetic analysis of the innate immune responses in wild-derived inbred strains of mice

The vertebrate immune system has evolved to recognize nucleic acids of bacterial and viral origin. Microbial DNA, as well as synthetic oligonucleotides based on these motifs, activates innate immune pathways mediated by the family of Toll-like receptors (TLR) initiating a cascade of signals in immune cells necessary for responses to pathogens. However, not all of the proteins that participate in TLR-mediated responses have been identified. In studies described herein, we observed significant variation in innate immune responses among selected wild-derived strains of mice. Specifically, we show that mice of MOLF/Ei, Czech/Ei, and MSM/Ms strains are hypo-responsive to polyinosinic-polycytidylic acid (poly(I:C)) because of a mutation in Tlr3. In addition, we discovered a hypo-response to cytosine guanine dinucleotide in MOLF/Ei mice and established that it is not linked to Tlr9, but to another locus. Further inquiry revealed that this hypo-response is transmitted as a monogenic dominant trait that can be mapped and cloned through positional cloning methods. These results suggest the existence of a novel molecule that can alter pro-inflammatory signals or activate additional signal transduction pathways. In addition, they support the wild-derived mouse strain as a forward genetic tool for the identification of novel immunological phenotypes.