RESUMEN
Type 1 Diabetes (T1D) is an autoimmune disease characterized by the pancreatic infiltration of immune cells resulting in T cell-mediated destruction of the insulin-producing beta cells. The successes of the Non-Obese Diabetic (NOD) mouse model have come in multiple forms including identifying key genetic and environmental risk factors e.g. Idd loci and effects of microorganisms including the gut microbiota, respectively, and how they may contribute to disease susceptibility and pathogenesis. Furthermore, the NOD model also provides insights into the roles of the innate immune cells as well as the B cells in contributing to the T cell-mediated disease. Unlike many autoimmune disease models, the NOD mouse develops spontaneous disease and has many similarities to human T1D. Through exploiting these similarities many targets have been identified for immune-intervention strategies. Although many of these immunotherapies did not have a significant impact on human T1D, they have been shown to be effective in the NOD mouse in early stage disease, which is not equivalent to trials in newly-diagnosed patients with diabetes. However, the continued development of humanized NOD mice would enable further clinical developments, bringing T1D research to a new translational level. Therefore, it is the aim of this review to discuss the importance of the NOD model in identifying the roles of the innate immune system and the interaction with the gut microbiota in modifying diabetes susceptibility. In addition, the role of the B cells will also be discussed with new insights gained through B cell depletion experiments and the impact on translational developments. Finally, this review will also discuss the future of the NOD mouse and the development of humanized NOD mice, providing novel insights into human T1D.
Asunto(s)
Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Tipo 1/inmunología , Inmunidad Innata , Células Secretoras de Insulina/inmunología , Ratones Endogámicos NOD/inmunología , Linfocitos T/inmunología , Animales , Autoinmunidad , Linfocitos B/inmunología , Linfocitos B/metabolismo , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Microbioma Gastrointestinal/inmunología , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Antígenos HLA/inmunología , Antígenos HLA/metabolismo , Humanos , Inmunoterapia , Insulina/inmunología , Ratones , Ratones Endogámicos NOD/genética , Ratones Transgénicos , Proteínas Adaptadoras de Señalización NOD/inmunología , Proteínas Adaptadoras de Señalización NOD/metabolismo , Ratas , Ratas Endogámicas BB , Transducción de Señal , Linfocitos T/metabolismo , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismoRESUMEN
Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are pattern-recognition receptors similar to toll-like receptors (TLRs). While TLRs are transmembrane receptors, NLRs are cytoplasmic receptors that play a crucial role in the innate immune response by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Based on their N-terminal domain, NLRs are divided into four subfamilies: NLRA, NLRB, NLRC, and NLRP. NLRs can also be divided into four broad functional categories: inflammasome assembly, signaling transduction, transcription activation, and autophagy. In addition to recognizing PAMPs and DAMPs, NLRs act as a key regulator of apoptosis and early development. Therefore, there are significant associations between NLRs and various diseases related to infection and immunity. NLR studies have recently begun to unveil the roles of NLRs in diseases such as gout, cryopyrin-associated periodic fever syndromes, and Crohn's disease. As these new associations between NRLs and diseases may improve our understanding of disease pathogenesis and lead to new approaches for the prevention and treatment of such diseases, NLRs are becoming increasingly relevant to clinicians. In this review, we provide a concise overview of NLRs and their role in infection, immunity, and disease, particularly from clinical perspectives.
Asunto(s)
Inmunidad Innata , Proteínas Adaptadoras de Señalización NOD/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Reconocimiento de Patrones/inmunología , Transducción de Señal , Autofagia/inmunología , Proteínas Portadoras , Humanos , Inflamasomas , Proteínas Adaptadoras de Señalización NOD/inmunología , Moléculas de Patrón Molecular Asociado a Patógenos , Receptores Citoplasmáticos y Nucleares/inmunología , Receptores Toll-Like/metabolismoRESUMEN
Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are pattern-recognition receptors similar to toll-like receptors (TLRs). While TLRs are transmembrane receptors, NLRs are cytoplasmic receptors that play a crucial role in the innate immune response by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Based on their N-terminal domain, NLRs are divided into four subfamilies: NLRA, NLRB, NLRC, and NLRP. NLRs can also be divided into four broad functional categories: inflammasome assembly, signaling transduction, transcription activation, and autophagy. In addition to recognizing PAMPs and DAMPs, NLRs act as a key regulator of apoptosis and early development. Therefore, there are significant associations between NLRs and various diseases related to infection and immunity. NLR studies have recently begun to unveil the roles of NLRs in diseases such as gout, cryopyrin-associated periodic fever syndromes, and Crohn's disease. As these new associations between NRLs and diseases may improve our understanding of disease pathogenesis and lead to new approaches for the prevention and treatment of such diseases, NLRs are becoming increasingly relevant to clinicians. In this review, we provide a concise overview of NLRs and their role in infection, immunity, and disease, particularly from clinical perspectives.
Asunto(s)
Humanos , Autofagia/inmunología , Proteínas Portadoras , Inmunidad Innata , Inflamasomas , Proteínas Adaptadoras de Señalización NOD/inmunología , Moléculas de Patrón Molecular Asociado a Patógenos , Receptores Citoplasmáticos y Nucleares/inmunología , Receptores de Reconocimiento de Patrones/inmunología , Transducción de Señal , Receptores Toll-Like/metabolismoRESUMEN
The composition of the microbiome in health and disease has only recently become a major research focus. Although it is clear that an imbalance or dysbiosis in the microbiota is associated with disease, its interrelatedness to disease penetrance is largely unknown. Inflammatory bowel disease (IBD) is an excellent disease in which to explore these questions because of the extensive genetic studies identifying disease susceptibility loci and the ability to easily sample the intestinal microbiota in IBD patients due to the accessibility of stool samples. In addition, mouse models of IBD have contributed to our understanding of the interrelatedness of the gut microbiota and genes associated with IBD. The power of the mouse studies is that multiple colitis models exist that can be used in combination with genetically modified mice that harbour deficiencies in IBD susceptibility genes. Collectively, these studies revealed that bacterial dysbiosis does occur in human IBD and in mouse colitis models. In addition, with an emphasis on immune genes, the mouse studies provided evidence that specific immune regulatory proteins associated with IBD influence the gut microbiota in a manner consistent with disease penetrance. In this review, we will discuss studies in both humans and mice that demonstrate the impact of immunodeficiences in interleukin-10, interleukin-17, nucleotide-binding oligomerization domain (NOD) 2, NOD-like receptor proteins 3 and 6, Toll-like receptor or IgA have on the interrelatedness between the composition of the gut microbiota and disease penetrance of IBD and its mouse models.
Asunto(s)
Colitis/inmunología , Colitis/microbiología , Disbiosis/inmunología , Microbioma Gastrointestinal/inmunología , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/microbiología , Animales , Modelos Animales de Enfermedad , Disbiosis/microbiología , Humanos , Deficiencia de IgA/inmunología , Deficiencia de IgA/microbiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Interleucina-10/deficiencia , Interleucina-10/inmunología , Ratones , Modelos Inmunológicos , Proteínas Adaptadoras de Señalización NOD/deficiencia , Proteínas Adaptadoras de Señalización NOD/inmunología , Penetrancia , Células Th17/inmunología , Receptores Toll-Like/inmunologíaRESUMEN
The NOD-like receptors (NLRs) are cytosolic pattern-recognition receptors, which are critically involved in mucosal immune defense. The association of the NLR, NOD2, with inflammatory bowel disease first pointed to the NLRs potential function as guardians of the intestinal barrier. Since then, several studies have emphasized the importance of NLRs in maintaining gut homeostasis and intestinal infections, and in shaping the microbiota. In this review, we will highlight the function of NLRs in intestinal inflammation.
Asunto(s)
Bacterias/metabolismo , Infecciones Bacterianas/metabolismo , Traslocación Bacteriana , Gastroenteritis/metabolismo , Mucosa Intestinal/metabolismo , Proteínas Adaptadoras de Señalización NOD/metabolismo , Transducción de Señal , Animales , Bacterias/inmunología , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Gastroenteritis/inmunología , Gastroenteritis/microbiología , Interacciones Huésped-Patógeno , Humanos , Inmunidad Mucosa , Inflamasomas/inmunología , Inflamasomas/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Proteínas Adaptadoras de Señalización NOD/inmunología , PermeabilidadRESUMEN
Objetivos: Revisar el efecto de los probióticos sobre parámetros relacionados no solo con la salud intestinal, sino con efectos sistémicos, especialmente sobre el sistema inmunitario y las infecciones. Resultados: Existen múltiples estudios y artículos publicados sobre probióticos en los que se evalúan efectos no exclusivamente intestinales, sino además más allá del intestino, sobre todo a nivel del sistema inmunitario y control de infecciones. Conclusiones: Aunque son necesarias más evidencias, todo apunta a que determinadas cepas probióticas ejercen efectos no solo a nivel local en el aparato digestivo, sino también a nivel sistémico, sobre todo a nivel de sistema inmune (AU)
Objectives: The aim of this article is to examine the effects of probiotics related to intestinal health as well as its systemic effects, principally on the immune system and infections. Results: There are multiple studies and articles published about probiotics in which not only are the effects on the intestinal tract investigated but also those outside the intestine, above all on the immune system and infections. Conclusions: Although more evidence is needed, it seems to be clear that some probiotic strains affect the digestive system not only at a local level, but also systemically, especially the immune system (AU)
Asunto(s)
Humanos , Probióticos/uso terapéutico , Microbiota/inmunología , Sistema Inmunológico , Infecciones/inmunología , Intestinos/inmunología , Receptores Toll-Like/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , LactobacillusRESUMEN
Nucleotide-binding oligomerization domain receptors (NOD-like receptors, NLRs) are intracellular proteins that are chiefly known for their critical functions in inflammatory responses and host defense against microbial pathogens. Several NLRs have been demonstrated to assemble inflammasomes or to engage transcriptional signaling cascades that result in the production of pro-inflammatory cytokines and bactericidal factors. In recent years, NLRs have also emerged as key regulators of early mammalian embryogenesis and reproduction. A subset of phylogenetically related NLRs represents a new class of maternal effect genes that are highly expressed in maturing oocytes and pre-implantation embryos. Mutations in several of these NLRs have been linked to hereditary reproductive defects and imprinting diseases. In this review, we discuss the expression profiles, the emerging functions and molecular mode of action of these NLRs with newly recognized roles at the interfaces of the immune and reproductive systems. In addition, we provide an overview of coding mutations in NLRs that have been associated with human reproductive diseases, and outline crucial outstanding questions in this emerging research field.
Asunto(s)
Inmunidad Innata/inmunología , Proteínas Adaptadoras de Señalización NOD/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Reproducción/fisiología , Animales , Humanos , Proteínas Adaptadoras de Señalización NOD/inmunología , Receptores Citoplasmáticos y Nucleares/inmunología , Transducción de SeñalRESUMEN
Innate immunity confers an immediate nonspecific mechanism of microbial recognition through germ line-encoded pattern recognition receptors (PRRs). Of these, Toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) have shaped our current understanding of innate regulation of adaptive immunity. It is now recognized that PRRs are paramount in instructing an appropriate adaptive immune response. Their ligands have been the focus of adjuvant research with the goal of generating modern vaccine combinations tailored to specific pathogens. In this review we will highlight the recent findings in the field of adjuvant research with a particular focus on the potential of TLR and NLR ligands as adjuvants and their influence on adaptive immune responses.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Proteínas Adaptadoras de Señalización NOD/agonistas , Receptores Toll-Like/agonistas , Vacunas/administración & dosificación , Inmunidad Adaptativa , Animales , Humanos , Inmunidad Innata , Proteínas Adaptadoras de Señalización NOD/inmunología , Receptores de Reconocimiento de Patrones/agonistas , Receptores de Reconocimiento de Patrones/inmunología , Receptores Toll-Like/inmunología , Vacunas/inmunologíaRESUMEN
The intestinal epithelium constitutes a dynamic physical barrier segregating the luminal content from the underlying mucosal tissue. Following injury, the epithelial integrity is restored by rapid migration of intestinal epithelial cells (IECs) across the denuded area in a process known as wound healing. Hence, through a sequence of events involving restitution, proliferation and differentiation of IECs the gap is resealed and homeostasis reestablished. Relapsing damage followed by healing of the inflamed mucosa is a hallmark of several intestinal disorders including inflammatory bowel diseases (IBD). While several regulatory peptides, growth factors and cytokines stimulate restitution of the epithelial layer after injury, recent evidence in the field underscores the contribution of innate immunity in controlling this process. In particular, nucleotide-binding and oligomerization domain-like receptors (NLRs) play critical roles in sensing the commensal microbiota, maintaining homeostasis, and regulating intestinal inflammation. Here, we review the process of intestinal epithelial tissue repair and we specifically focus on the impact of NLR-mediated signaling mechanisms involved in governing epithelial wound healing during disease.
Asunto(s)
Homeostasis , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Proteínas Adaptadoras de Señalización NOD/inmunología , Animales , Humanos , Inmunidad Innata , Inflamasomas/análisis , Inflamasomas/inmunología , Proteínas Adaptadoras de Señalización NOD/análisis , Receptores Toll-Like/análisis , Receptores Toll-Like/inmunología , Cicatrización de HeridasRESUMEN
Obesity and Type 2 diabetes are leading health problems which are characterized by low-grade inflammation with an increase in inflammatory cytokines along with the change in the gut microbiota population. Toll like Receptors (TLRs) and NOD like Receptors (NLRs) are very prominent pathogen recognition receptors, which play a significant role in the innate immune system. Both TLRs and NLRs pathways are mediated through different adaptor proteins; commonly found to activate the NF-kB, which induces the expression of proinflammatory cytokines. It has been suggested that TLRs and NLRs have a significant role in the pathogenesis of inflammation mediated insulin resistance, which further develops metabolic complications. TLRs mediated mechanism for insulin resistance involves activation through TLR ligands such as increased free fatty acids and lipid derivatives from adipocytes as well as the skeletal muscles. Moreover, gut microbiota alteration in the type 2 diabetes also plays a key role by increasing the plasma LPS levels, which specifically activates TLR4 and provokes the inflammation mediated insulin resistance. NOD1 and NOD2 are involved in the pathogenesis of diabetes, possibly through the recognition of the gut microbiota. Gut microbiota modulation by antibiotics plays a crucial role in increasing insulin sensitivity, possibly through the TLRs and NLRs mediated signaling responses, which suggest future therapeutic approaches for obesity, insulin resistance and type 2 diabetes. In this review, we focused on the interdependent role of TLRs and NLRs in metabolic diseases and their cross talk for the pathogenesis of inflammatory diseases.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Mucosa Gástrica/metabolismo , Inflamación/metabolismo , Resistencia a la Insulina , Proteínas Adaptadoras de Señalización NOD/metabolismo , Obesidad/metabolismo , Receptores Toll-Like/metabolismo , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/fisiopatología , Mucosa Gástrica/inmunología , Humanos , Inmunidad Innata , Inflamación/inmunología , Inflamación/fisiopatología , Resistencia a la Insulina/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , Obesidad/complicaciones , Obesidad/inmunología , Obesidad/fisiopatología , Receptor Cross-Talk , Receptores de Reconocimiento de Patrones , Transducción de Señal , Receptores Toll-Like/inmunologíaRESUMEN
Entry of bacteria into host cells is an important virulence mechanism. Through peptidoglycan recognition, the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 enable detection of intracellular bacteria and promote their clearance through initiation of a pro-inflammatory transcriptional programme and other host defence pathways, including autophagy. Recent findings have expanded the scope of the cellular compartments monitored by NOD1 and NOD2 and have elucidated the signalling pathways that are triggered downstream of NOD activation. In vivo, NOD1 and NOD2 have complex roles, both during bacterial infection and at homeostasis. The association of alleles that encode constitutively active or constitutively inactive forms of NOD2 with different diseases highlights this complexity and indicates that a balanced level of NOD signalling is crucial for the maintenance of immune homeostasis.
Asunto(s)
Inflamación/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , Inmunidad Adaptativa , Animales , Autofagia , Infecciones Bacterianas/inmunología , Humanos , Inmunidad Innata , Intestinos/inmunología , Neoplasias/inmunología , Proteínas Adaptadoras de Señalización NOD/química , Proteínas Adaptadoras de Señalización NOD/fisiología , Peptidoglicano/inmunología , Transducción de SeñalRESUMEN
BACKGROUND: Pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs), recognize microbial components and trigger a host defense response. Respiratory tract infections are common causes of asthma exacerbations, suggesting a role for PRRs in this process. The present study aimed to examine the expression and function of PRRs on human airway smooth muscle cells (HASMCs). METHODS: Expression of TLR, NLR and RLR mRNA and proteins was determined using real-time RT-PCR, flow cytometry and immunocytochemistry. The functional responses to ligand stimulation were investigated in terms of cytokine and chemokine release, cell surface marker expression, proliferation and proteins regulating the contractile state. RESULTS: HASMCs expressed functional TLR2, TLR3, TLR4, TLR7 and NOD1. Stimulation with the corresponding agonists Pam3CSK4, poly(I:C), LPS, R-837 and iE-DAP, respectively, induced IL-6, IL-8 and GM-CSF release and up-regulation of ICAM-1 and HLA-DR, while poly(I:C) also affected the release of eotaxin and RANTES. The proliferative response was slightly increased by LPS. Stimulation, most prominently with poly(I:C), down-regulated myosin light chain kinase and cysteinyl leukotriene 1 receptor expression and up-regulated ß2-adrenoceptor expression. No effects were seen for agonist to TLR2/6, TLR5, TLR8, TLR9, NOD2 or RIG-I/MDA-5. CONCLUSION: Activation of TLR2, TLR3, TLR4, TLR7 and NOD1 favors a synthetic phenotype, characterized by an increased ability to release inflammatory mediators, acquire immunomodulatory properties by recruiting and interacting with other cells, and reduce the contractile state. The PRRs might therefore be of therapeutic use in the management of asthma and infection-induced disease exacerbations.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Miocitos del Músculo Liso/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , ARN Mensajero/genética , Receptores Toll-Like/inmunología , Tráquea/inmunología , Aminoquinolinas/farmacología , Biomarcadores/metabolismo , Proliferación Celular , Citocinas/biosíntesis , Citocinas/inmunología , Regulación de la Expresión Génica/inmunología , Humanos , Imiquimod , Inmunidad Innata , Lipopéptidos/farmacología , Lipopolisacáridos/farmacología , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Proteínas Adaptadoras de Señalización NOD/agonistas , Proteínas Adaptadoras de Señalización NOD/genética , Poli I-C/farmacología , ARN Mensajero/inmunología , Transducción de Señal , Receptores Toll-Like/agonistas , Receptores Toll-Like/genética , Tráquea/citología , Tráquea/efectos de los fármacosRESUMEN
Ilya Metchnikoff's use of starfish larvae to discover phagocytosis, and Bruno Lemaitre's and Jules Hoffmann's identification of host defence functions for Drosophila Toll provide compelling examples of the utility of model organisms for discovery of human innate immune pathways. Bruce Beutler's mapping of lipopolysaccharide non-responsiveness in C3H/HeJ mice to the Toll-like Receptor 4 gene similarly highlights the power of the mouse as a model. Models have limitations however, and characterising the functional relevance of human innate immune responses not conserved in the mouse presents both a challenge and an opportunity. Here we review differences between human and mouse Toll-like Receptors and inflammasome-forming Nod-like Receptors in repertoire, regulation and function, highlighting the significance of these differences for human innate immunity.
Asunto(s)
Inmunidad Innata , Inflamasomas/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , Receptores Toll-Like/inmunología , Animales , Humanos , Ratones , Ratones Endogámicos C3HRESUMEN
The present review aims to provide insight into the complex interactions between the host and Pseudomonas aeruginosa-an opportunistic microbial agent causing skin infections. Heat, humidity and skin pH are among the factors beneficial for the development of this Gram-negative agent. To cause infection, Pseudomonas aeruginosa should first overcome the primary mechanisms of defense including the cell elements and humoral factors of the skin, as well as non-specific responses-phagocytosis, inflammation, acute phase response. All they are analysed with emphasis on the fact that their detailed understanding would help revealing their potential and allow for their efficient control. The microorganism, being more alterable and more flexible than the host, uses stealth strategies and modes of life. The review goes over the arsenal of virulence factors, used by Pseudomonas aeruginosa to attack the host defense mechanisms. The bacterial pathogenic strategies for invasion, resulting in collapse of skin defense are analysed. Several novel therapeutic approached to Pseudomonas aeruginosa skin infections are briefly reviewed.
Asunto(s)
Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/patogenicidad , Piel , Péptidos Catiónicos Antimicrobianos/inmunología , Humanos , Inmunidad Innata , FN-kappa B/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/inmunología , Piel/citología , Piel/inmunología , Piel/microbiología , Receptores Toll-Like/inmunología , Factores de VirulenciaRESUMEN
The outcome of natural infections with pathogenic mycobacteria can range from early asymptomatic clearance through latent infection to clinical disease. Different host and pathogen-specific factors have been implicated in determining the outcome of these infections; however, it is clear that the interaction of mycobacteria with the innate and acquired components of the immune system plays a central role. Specifically, the recognition of mycobacterial components by innate immune cells through different pathogen recognition receptors (PPRs) induces a cytokine response that can promote early control of the infection. In fact, in the majority of individuals that come into contact with mycobacteria, this response is enough to control the infection. Among PRRs, Toll-like receptors (TLRs), Nucleotide Oligomerization Domain (NOD)-like receptors, and C-type lectins have all been implicated in recognition of mycobacteria and in the initiation of the cytokine response. Defining the mechanisms by which distinct mycobacterial components and their receptors stimulate the immune response is an area of intense research.
Asunto(s)
Citocinas/fisiología , Infecciones por Mycobacterium/inmunología , Susceptibilidad a Enfermedades , Eicosanoides/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Interleucinas/inmunología , Lectinas Tipo C/inmunología , Macrófagos/inmunología , Macrófagos/microbiología , Modelos Inmunológicos , Infecciones por Mycobacterium/microbiología , Infecciones por Mycobacterium/patología , Mycobacterium tuberculosis/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , Fagocitosis , Subgrupos de Linfocitos T/inmunología , Receptores Toll-Like/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Innate instruction of adaptive immunity was proposed more than 20 years ago as a mechanism by which long-lived lymphocyte responses are targeted to appropriate antigens. At the time Charles Janeway proposed this theory, most of the innate immune receptors were unknown, and the pivotal role of the dendritic cell in instructing T cell priming was debated. There is now overwhelming evidence that the innate and adaptive branches of the immune system must interact to generate immunity. Much of this work has focused on families of innate immune receptors called pattern recognition receptors (PRRs) on dendritic cells, which translate these inflammatory triggers into productive T cell responses. Nevertheless, we are only beginning to understand how these defence molecules shape the generation of immunity. We review the varied roles of one class of PRRs, the NOD-like receptors (NLRs), in immune responses and propose a new model in which adaptive immunity requires coordinated PRR activation within the dendritic cell.
Asunto(s)
Células Dendríticas/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , Receptores Acoplados a Proteínas G/inmunología , Receptores de Reconocimiento de Patrones/inmunología , Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , Humanos , Inmunidad Innata , Activación de LinfocitosRESUMEN
Pattern recognition receptors recognize signals originating from pathogens and comprise a large part of the arsenal in innate immune responses. The NOD-like receptors (NLRs) are one particular class of these receptors that survey the cytoplasm for signs of pathogen invasion. Upon detection, they trigger the formation of a macromolecular complex called the inflammasome that is required for elimination of the pathogen, as well as amplifying a pro-inflammatory response. Although the core machinery has been defined, recent data emphasize the complexity of how NLR inflammasomes function. Here, we highlight new discoveries that reveal how precisely fine-tuned NLR inflammasome functions are, and how that may be modulated by antagonistic effects of concomitant inflammasome activation as well as novel regulatory factors.
Asunto(s)
Caspasas/inmunología , Inmunidad Innata , Inflamasomas/inmunología , Complejos Multiproteicos/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , Animales , Caspasas Iniciadoras , Citosol/inmunología , Humanos , Ratones , Transducción de SeñalRESUMEN
NLR proteins are innate immune sensors that respond to microbial infection. Upon pathogen infection, some NLR proteins form large complexes, called inflammasomes, which activate caspase-1 and induce the production of active IL-1ß and IL-18. Activation of inflammasomes can also lead to an inflammatory cell death program, named pyroptosis. In this review, we will discuss the role of various NLR proteins in sensing different viral infections, as well as the strategies used by several RNA and DNA viruses to counteract the antiviral effects of NLR-dependent inflammasomes.
Asunto(s)
Inmunidad Innata/inmunología , Inflamasomas/inmunología , Proteínas Adaptadoras de Señalización NOD/inmunología , Transducción de Señal/inmunología , Virosis/inmunología , Animales , HumanosRESUMEN
Despite our efforts to halt the increase and spread of antimicrobial resistance, bacteria continue to become less susceptible to antimicrobial drugs over time, and rates of discovery for new antibiotics are declining. Thus, it is essential to explore new paradigms for anti-infective therapy. One promising approach involves host-directed immunomodulatory therapies, whereby natural mechanisms in the host are exploited to enhance therapeutic benefit. The objective is to initiate or enhance protective antimicrobial immunity while limiting inflammation-induced tissue injury. A range of potential immune modulators have been proposed, including innate defence regulator peptides and agonists of innate immune components such as Toll-like receptors and NOD-like receptors.