RESUMEN
OBJECTIVE: In the management of patients with IBD, there is a need to identify prognostic markers and druggable biological pathways to improve mucosal repair and probe the efficacy of tumour necrosis factor alpha biologics. Vnn1 is a pantetheinase that degrades pantetheine to pantothenate (vitamin B5, a precursor of coenzyme A (CoA) biosynthesis) and cysteamine. Vnn1 is overexpressed by inflamed colonocytes. We investigated its contribution to the tolerance of the intestinal mucosa to colitis-induced injury. DESIGN: We performed an RNA sequencing study on colon biopsy samples from patients with IBD stratified according to clinical severity and modalities of treatment. We generated the VIVA mouse transgenic model, which specifically overexpresses Vnn1 on intestinal epithelial cells and explored its susceptibility to colitis. We developed a pharmacological mimicry of Vnn1 overexpression by administration of Vnn1 derivatives. RESULTS: VNN1 overexpression on colonocytes correlates with IBD severity. VIVA mice are resistant to experimentally induced colitis. The pantetheinase activity of Vnn1 is cytoprotective in colon: it enhances CoA regeneration and metabolic adaptation of colonocytes; it favours microbiota-dependent production of short chain fatty acids and mostly butyrate, shown to regulate mucosal energetics and to be reduced in patients with IBD. This prohealing phenotype is recapitulated by treating control mice with the substrate (pantethine) or the products of pantetheinase activity prior to induction of colitis. In severe IBD, the protection conferred by the high induction of VNN1 might be compromised because its enzymatic activity may be limited by lack of available substrates. In addition, we identify the elevation of indoxyl sulfate in urine as a biomarker of Vnn1 overexpression, also detected in patients with IBD. CONCLUSION: The induction of Vnn1/VNN1 during colitis in mouse and human is a compensatory mechanism to reinforce the mucosal barrier. Therefore, enhancement of vitamin B5-driven metabolism should improve mucosal healing and might increase the efficacy of anti-inflammatory therapy.
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Colitis , Enfermedades Inflamatorias del Intestino , Humanos , Ratones , Animales , Colitis/metabolismo , Colon/patología , Mucosa Intestinal/metabolismo , Enfermedades Inflamatorias del Intestino/genética , Ácidos Grasos Volátiles/metabolismo , Vitaminas , Sulfato de Dextran , Modelos Animales de EnfermedadRESUMEN
Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) driven by viruses or bacteria, as well as in numerous immune-mediated disorders. Histone citrullination by the enzyme peptidylarginine deiminase 4 (PAD4) and the consequent decondensation of chromatin are hallmarks in the induction of NETs. Nevertheless, additional histone modifications that may govern NETosis are largely overlooked. Herein, we show that histone deacetylases (HDACs) play critical roles in driving NET formation in human and mouse neutrophils. HDACs belonging to the zinc-dependent lysine deacetylases family are necessary to deacetylate histone H3, thus allowing the activity of PAD4 and NETosis. Of note, HDAC inhibition in mice protects against microbial-induced pneumonia and septic shock, decreasing NETosis and inflammation. Collectively, our findings illustrate a new fundamental step that governs the release of NETs and points to HDAC inhibitors as therapeutic agents that may be used to protect against ARDS and sepsis.
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Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites.
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COVID-19/patología , Interferones/metabolismo , Sistema Respiratorio/virología , Índice de Severidad de la Enfermedad , Factores de Edad , Envejecimiento/patología , COVID-19/genética , COVID-19/inmunología , Células Epiteliales/patología , Células Epiteliales/virología , Regulación de la Expresión Génica , Humanos , Interferones/genética , Leucocitos/patología , Leucocitos/virología , Pulmón/patología , Pulmón/virología , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , Carga ViralRESUMEN
A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.
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Interacciones Huésped-Patógeno , Inmunidad Celular , Neumonía Viral/etiología , Neumonía Viral/metabolismo , Receptor Notch4/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Anfirregulina/farmacología , Animales , Biomarcadores , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunohistoquímica , Inmunomodulación/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Virus de la Influenza A/fisiología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Ratones , Ratones Transgénicos , Neumonía Viral/patología , Receptor Notch4/antagonistas & inhibidores , Receptor Notch4/genética , Índice de Severidad de la EnfermedadRESUMEN
The COVID-19 outbreak driven by SARS-CoV-2 has caused more than 2.5 million deaths globally, with the most severe cases characterized by over-exuberant production of immune-mediators, the nature of which is not fully understood. Interferons of the type I (IFN-I) or type III (IFN-III) families are potent antivirals, but their role in COVID-19 remains debated. Our analysis of gene and protein expression along the respiratory tract shows that IFNs, especially IFN-III, are over-represented in the lower airways of patients with severe COVID-19, while high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity; also, IFN expression varies with abundance of the cell types that produce them. Our data point to a dynamic process of inter- and intra-family production of IFNs in COVID-19, and suggest that IFNs play opposing roles at distinct anatomical sites.
RESUMEN
Viral infections of the lower respiratory tract are a leading cause of mortality. Mounting evidence indicates that most severe cases are characterized by aberrant immune responses and do not depend on viral burden. In this study, we assessed how type III interferons (IFN-λ) contribute to the pathogenesis induced by RNA viruses. We report that IFN-λ is present in the lower, but not upper, airways of patients with coronavirus disease 2019 (COVID-19). In mice, we demonstrate that IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA induces barrier damage, causing susceptibility to lethal bacterial superinfections. These findings provide a strong rationale for rethinking the pathophysiological role of IFN-λ and its possible use in clinical practice against endemic viruses, such as influenza virus as well as the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
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Betacoronavirus , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/metabolismo , Células Dendríticas/metabolismo , Interferones/fisiología , Pulmón/metabolismo , Pulmón/patología , Neumonía Viral/inmunología , Neumonía Viral/metabolismo , Animales , Líquido del Lavado Bronquioalveolar/inmunología , COVID-19 , Proliferación Celular , Citocinas/metabolismo , Humanos , Interferón Tipo I/metabolismo , Interferones/metabolismo , Pulmón/inmunología , Ratones , Ratones Endogámicos C57BL , Nasofaringe/inmunología , Pandemias , Poli I-C/administración & dosificación , Mucosa Respiratoria/patología , SARS-CoV-2 , Transducción de Señal , Infecciones Estafilocócicas/metabolismo , Sobreinfección , Receptor Toll-Like 3/metabolismo , Interferón lambdaRESUMEN
Type III IFNs, or IFN-λ, are the newest members of the IFN family and were long believed to play roles that were redundant with those of type I IFNs. However, IFN-λ displays unique traits that delineate them as primary protectors of barrier integrity at mucosal sites. This unique role stems both from the restricted expression of IFN-λ receptor, confined to epithelial cells and to a limited pool of immune cells, and from unique immunomodulatory properties of IFN-λ. Here, we discuss recent findings that establish the unique capacity of IFN-λ to act at the barriers of the host to balance tissue tolerance and immune resistance against viral and bacterial challenges.
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Bacterias/inmunología , Tolerancia Inmunológica/inmunología , Interferones/inmunología , Virus/inmunología , Animales , Células Epiteliales/inmunología , Células Epiteliales/microbiología , Células Epiteliales/virología , Humanos , Interferón lambdaRESUMEN
Phosphate is an essential macronutrient required for cell growth and division. Pho84 is the major high-affinity cell-surface phosphate importer of Saccharomyces cerevisiae and a crucial element in the phosphate homeostatic system of this model yeast. We found that loss of Candida albicans Pho84 attenuated virulence in Drosophila and murine oropharyngeal and disseminated models of invasive infection, and conferred hypersensitivity to neutrophil killing. Susceptibility of cells lacking Pho84 to neutrophil attack depended on reactive oxygen species (ROS): pho84-/- cells were no more susceptible than wild type C. albicans to neutrophils from a patient with chronic granulomatous disease, or to those whose oxidative burst was pharmacologically inhibited or neutralized. pho84-/- mutants hyperactivated oxidative stress signalling. They accumulated intracellular ROS in the absence of extrinsic oxidative stress, in high as well as low ambient phosphate conditions. ROS accumulation correlated with diminished levels of the unique superoxide dismutase Sod3 in pho84-/- cells, while SOD3 overexpression from a conditional promoter substantially restored these cells' oxidative stress resistance in vitro. Repression of SOD3 expression sharply increased their oxidative stress hypersensitivity. Neither of these oxidative stress management effects of manipulating SOD3 transcription was observed in PHO84 wild type cells. Sod3 levels were not the only factor driving oxidative stress effects on pho84-/- cells, though, because overexpressing SOD3 did not ameliorate these cells' hypersensitivity to neutrophil killing ex vivo, indicating Pho84 has further roles in oxidative stress resistance and virulence. Measurement of cellular metal concentrations demonstrated that diminished Sod3 expression was not due to decreased import of its metal cofactor manganese, as predicted from the function of S. cerevisiae Pho84 as a low-affinity manganese transporter. Instead of a role of Pho84 in metal transport, we found its role in TORC1 activation to impact oxidative stress management: overexpression of the TORC1-activating GTPase Gtr1 relieved the Sod3 deficit and ROS excess in pho84-/- null mutant cells, though it did not suppress their hypersensitivity to neutrophil killing or hyphal growth defect. Pharmacologic inhibition of Pho84 by small molecules including the FDA-approved drug foscarnet also induced ROS accumulation. Inhibiting Pho84 could hence support host defenses by sensitizing C. albicans to oxidative stress.
Asunto(s)
Candida albicans/patogenicidad , Candidiasis/metabolismo , Estrés Oxidativo/fisiología , Simportadores de Protón-Fosfato/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Transporte Biológico/fisiología , Drosophila , Proteínas Fúngicas/metabolismo , Humanos , Ratones , Fosfatos/metabolismo , Transducción de Señal/fisiología , VirulenciaRESUMEN
Type III interferons (IFNs) (or IFN-λ) are the latest addition to the IFN family. Even though they share little protein homology with type I IFN, both exhibit remarkable functional similarities: each can be induced in response to viral infections, and both lead to Janus kinases (JAK) and signal transducer and activator of transcription (STAT) activation. The JAK/STAT pathway induces antiviral responses and IFN-stimulated gene transcription. However, despite the similarities in their effector functions with type I IFNs, IFN-λ also has a non-redundant role in protecting barrier organs: epithelial cells preferentially produce IFN-λ rather than type I IFNs; and interferon lambda receptor 1 (IFNLR1), the specific receptor for IFN-λ, is highly expressed on cells of epithelial lineage. Thus far, IFN-λ has been considered mainly as an epithelial cytokine, which restricts viral replication in epithelial cells and constitutes an added layer of protection at mucosal sites. However, it is now increasingly recognized that IFNLR1 is expressed broadly, and that immune cells such as neutrophils and dendritic cells also respond to IFN-λ. Moreover, in many in vivo models, IFN-λ modulates immune cell functions and thereby configures itself less as a cytokine that is only specific to the epithelium, and more as a cytokine that directly controls the inflammatory response at mucosal sites. Here, we critically review the recent literature on immune modulatory roles for IFN-λ, and distinguish between the direct and indirect effects of this IFN on immune cell functions in different inflammatory settings.
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Nuclear factor of activated T cells (NFAT) is activated in innate immune cells downstream of pattern recognition receptors, but little is known about NFAT's functions in innate immunity compared with adaptive immunity. We show that early activation of NFAT balances the two major phases of the innate response to Candida albicans skin infections: the protective containment (abscess) and the elimination (expulsion) phases. During the early containment phase, transforming growth factor-ß (TGF-ß) induces the deposit of collagen around newly recruited polymorphonuclear cells to prevent microbial spreading. During the elimination phase, interferon-γ (IFN-γ) blocks differentiation of fibroblasts into myofibroblasts by antagonizing TGF-ß signaling. IFN-γ also induces the formation of plasmin that, in turn, promotes abscess capsule digestion and skin ulceration for microbial discharge. NFAT controls innate IFN-γ production and microbial expulsion. This cross-talk between the innate immune and the fibrinolytic systems also occurs during infection with Staphylococcus aureus and is a protective response to minimize tissue damage and optimize pathogen elimination.
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Interferon-λ (IFN-λ) is a central regulator of mucosal immunity; however, its signaling specificity relative to that of type I interferons is poorly defined. IFN-λ can induce antiviral interferon-stimulated genes (ISGs) in epithelia, while the effect of IFN-λ in non-epithelial cells remains unclear. Here we report that neutrophils responded to IFN-λ. We found that in addition to inducing ISG transcription, IFN-λ (but not IFN-ß) specifically activated a translation-independent signaling pathway that diminished the production of reactive oxygen species and degranulation in neutrophils. In mice, IFN-λ was elicited by enteric viruses and acted on neutrophils to decrease oxidative stress and intestinal damage. Thus, IFN-λ acted as a unique immunomodulatory agent by modifying transcriptional and non-translational neutrophil responses, which might permit a controlled development of the inflammatory process.
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Gastroenteritis/etiología , Gastroenteritis/metabolismo , Interferón gamma/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Animales , Análisis por Conglomerados , Modelos Animales de Enfermedad , Gastroenteritis/patología , Expresión Génica , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Intestinos/patología , Ratones , Ratones Noqueados , Microbiota , Estrés Oxidativo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismoRESUMEN
The skin is a barrier organ that interacts with the external environment. Being continuously exposed to potential microbial invasion, the dermis and epidermis home a variety of immune cells in both homeostatic and inflammatory conditions. Tools to obtain skin cell release for cytofluorimetric analyses are, therefore, very useful in order to study the complex network of immune cells residing in the skin and their response to microbial stimuli. Here, we describe an efficient methodology for the digestion of mouse skin to rapidly and efficiently obtain single-cell suspensions. This protocol allows maintenance of maximum cell viability without compromising surface antigen expression. We also describe how to take and digest skin samples from different anatomical locations, such as the ear, trunk, tail, and footpad. The obtained suspensions are then stained and analyzed by flow cytometry to discriminate between different leukocyte populations.
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Células Epidérmicas , Piel/citología , Animales , Biomarcadores/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Separación Celular , Colagenasas/farmacología , Células Dendríticas/citología , Células Dendríticas/metabolismo , Citometría de Flujo/métodos , Macrófagos/citología , Macrófagos/metabolismo , Metaloproteinasa 8 de la Matriz/farmacología , Ratones , Piel/efectos de los fármacos , Piel/metabolismo , Fenómenos Fisiológicos de la Piel , Suspensiones , Termolisina/farmacologíaRESUMEN
Dendritic cells (DCs) use pattern recognition receptors to detect microorganisms and activate protective immunity. These cells and receptors are thought to operate in an all-or-nothing manner, existing in an immunologically active or inactive state. Here, we report that encounters with microbial products and self-encoded oxidized phospholipids (oxPAPC) induce an enhanced DC activation state, which we call "hyperactive." Hyperactive DCs induce potent adaptive immune responses and are elicited by caspase-11, an enzyme that binds oxPAPC and bacterial lipopolysaccharide (LPS). oxPAPC and LPS bind caspase-11 via distinct domains and elicit different inflammasome-dependent activities. Both lipids induce caspase-11-dependent interleukin-1 release, but only LPS induces pyroptosis. The cells and receptors of the innate immune system can therefore achieve different activation states, which may permit context-dependent responses to infection.
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Inmunidad Adaptativa , Caspasas/inmunología , Células Dendríticas/inmunología , Interleucina-1beta/metabolismo , Lipopolisacáridos/inmunología , Fosfolípidos/metabolismo , Receptores de Reconocimiento de Patrones/inmunología , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Caspasas/genética , Caspasas Iniciadoras , Muerte Celular/inmunología , Células Dendríticas/metabolismo , Inmunidad Innata , Inflamasomas/inmunología , Ratones , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Receptores de Reconocimiento de Patrones/genética , Receptor Toll-Like 4/agonistas , Receptor Toll-Like 4/metabolismoRESUMEN
The ability of the immune system to give rise to an effective response against pathogens while maintaining tolerance towards self-tissues has always been an object of keen interest for immunologist. Over the years, different theories have been proposed to explain if and how the immune system is able to discriminate between self and non-self, including the Infectious Non-self theory from Charles Janeway and Polly Matzinger's Danger theory. Nowadays we know Janeway's theory is largely true, however the immune system does respond to injured, stressed and necrotic cells releasing danger signals (DAMPs) with a potent inflammatory response. To avoid unwanted prolonged autoimmune reactions, though, danger-induced inflammation should be tightly regulated. In the present review we discuss how prototypic DAMPs are able to induce inflammation and the peculiarity of danger-induced inflammation, as opposed to a complete immune response to fight pathogen invasions.
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Bacterias/inmunología , Inflamación/inmunología , Inflamación/microbiología , Animales , Proteína HMGB1/metabolismo , Humanos , Inflamasomas/metabolismo , Inflamación/patología , Receptores de Reconocimiento de Patrones/metabolismo , Receptores Toll-Like/metabolismoRESUMEN
The first-generation smallpox vaccine was based on live vaccinia virus (VV) and it successfully eradicated the disease worldwide. Therefore, it was not administered any more after 1980, as smallpox no longer existed as a natural infection. However, emerging threats by terrorist organisations has prompted new programmes for second-generation vaccine development based on attenuated VV strains, which have been shown to cause rare but serious adverse events in immunocompromised patients. Considering the closely related animal poxviruses that might also be used as bioweapons, and the increasing number of unvaccinated young people and AIDS-affected immunocompromised subjects, a safer and more effective smallpox vaccine is still required. New avipoxvirus-based vectors should improve the safety of conventional vaccines, and protect from newly emerging zoonotic orthopoxvirus diseases and from the threat of deliberate release of variola or monkeypox virus in a bioterrorist attack. In this study, DNA and fowlpox recombinants expressing the L1R, A27L, A33R and B5R genes were constructed and evaluated in a pre-clinical trial in mouse, following six prime/boost immunisation regimens, to compare their immunogenicity and protective efficacy against a challenge with the lethal VV IHD-J strain. Although higher numbers of VV-specific IFNγ-producing T lymphocytes were observed in the protected mice, the cytotoxic T-lymphocyte response and the presence of neutralising antibodies did not always correlate with protection. In spite of previous successful results in mice, rabbits and monkeys, where SIV/HIV transgenes were expressed by the fowlpox vector, the immune response elicited by these recombinants was low, and most of the mice were not protected.
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Virus de la Viruela de las Aves de Corral/genética , Mpox/prevención & control , Vacuna contra Viruela/inmunología , Vacunas de ADN/inmunología , Virus Vaccinia/inmunología , Proteínas Virales/inmunología , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Citotoxicidad Inmunológica , Femenino , Vectores Genéticos , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos BALB C , Mpox/inmunología , Vacuna contra Viruela/administración & dosificación , Vacuna contra Viruela/genética , Linfocitos T/inmunología , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genética , Virus Vaccinia/genética , Proteínas Virales/genéticaRESUMEN
Natural killer (NK) cells have antitumor, antiviral, and antibacterial functions, and efforts are being made to manipulate them in immunotherapeutic approaches. However, their activation mechanisms remain poorly defined, particularly during bacterial infections. Here, we show that upon lipopolysaccharide or E. coli exposure, dendritic cells (DCs) produce three cytokines-interleukin 2 (IL-2), IL-18, and interferon ß (IFN-ß)-necessary and sufficient for NK cell activation. IFN-ß enhances NK cell activation by inducing IL-15 and IL-15 receptor α not only in DCs but, surprisingly, also in NK cells. This process allows the transfer of IL-15 on NK cell surface and its cis presentation. cis-presented NK cell-derived and trans-presented DC-derived IL-15 contribute equally to optimal NK cell activation.
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Células Dendríticas/inmunología , Interleucina-15/inmunología , Células Asesinas Naturales/inmunología , Lipopolisacáridos/farmacología , Animales , Células Dendríticas/citología , Células Dendríticas/metabolismo , Humanos , Inflamación/inmunología , Interleucina-15/metabolismo , Células Asesinas Naturales/citología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Lipopolisacáridos/inmunología , Ratones , Ratones Noqueados , Ratones Transgénicos , Transducción de Señal , Relación Estructura-ActividadRESUMEN
Conventional DCs are an extremely heterogeneous cell population that comprises several different subsets. A major distinction can be made between lymphoid-resident DCs that are present in the lymphoid tissues and the blood and migratory DCs that reside in the nonlymphoid tissues and migrate to the lymph nodes, both in homeostatic conditions and during the course of an infection. Migratory DCs differ from tissue to tissue but share the unique ability to transport antigens to the draining lymph nodes-in particular, tissue-restricted antigens in homeostatic conditions and microbial antigens after an infection. Recently, steady-state migratory DCs have gained much attention after the discovery of their high tolerogenic potential. The purpose of this review is to give a picture of the recent finding regarding steady-state migratory DCs with particular interest in their role in inducing T cell tolerance.
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Células Dendríticas/inmunología , Tolerancia Inmunológica , Linfocitos T/inmunología , Animales , Antígenos CD/análisis , Movimiento Celular , Humanos , Cadenas alfa de Integrinas/análisis , Pulmón/inmunología , Piel/inmunologíaRESUMEN
There is evidence that dendritic cells (DCs) induce peripheral tolerance. Nevertheless, it is not known whether immature DCs in general are able to tolerize CD4(+) T cells or if this is a prerogative of specialized subtypes. Here we show that, when autoantigen presentation is extended to all conventional mouse DCs, immature lymphoid tissue resident DCs are unable to induce autoantigen-specific regulatory T (iTreg) cell conversion. In contrast, this is an exclusive prerogative of steady-state migratory DCs. Because only lymph nodes host migratory DCs, iTreg cells develop and are retained solely in lymph nodes, and not in the spleen. Mechanistically, in cutaneous lymph nodes, DC-derived CCL22 contributes to the retention of iTreg cells. The importance of the local generation of iTreg cells is emphasized by their essential role in preventing autoimmunity.
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Autoinmunidad , Movimiento Celular , Células Dendríticas/fisiología , Tolerancia Inmunológica/fisiología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad/genética , Autoinmunidad/inmunología , Autoinmunidad/fisiología , Movimiento Celular/genética , Movimiento Celular/fisiología , Células Cultivadas , Proteínas de Unión al ADN/genética , Células Dendríticas/metabolismo , Femenino , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Tejido Linfoide/citología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/fisiología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/fisiologíaRESUMEN
Inflammation is a multistep process triggered when innate immune cells - for example, DCs - sense a pathogen or injured cell or tissue. Edema formation is one of the first steps in the inflammatory response; it is fundamental for the local accumulation of inflammatory mediators. Injection of LPS into the skin provides a model for studying the mechanisms of inflammation and edema formation. While it is known that innate immune recognition of LPS leads to activation of numerous transcriptional activators, including nuclear factor of activated T cells (NFAT) isoforms, the molecular pathways that lead to edema formation have not been determined. As PGE2 regulates many proinflammatory processes, including swelling and pain, and it is induced by LPS, we hypothesized that PGE2 mediates the local generation of edema following LPS exposure. Here, we show that tissue-resident DCs are the main source of PGE2 and the main controllers of tissue edema formation in a mouse model of LPS-induced inflammation. LPS exposure induced expression of microsomal PGE synthase-1 (mPGES-1), a key enzyme in PGE2 biosynthesis. mPGES-1 activation, PGE2 production, and edema formation required CD14 (a component of the LPS receptor) and NFAT. Therefore, tissue edema formation induced by LPS is DC and CD14/NFAT dependent. Moreover, DCs can regulate free antigen arrival at the draining lymph nodes by controlling edema formation and interstitial fluid pressure in the presence of LPS. We therefore suggest that the CD14/NFAT/mPGES-1 pathway represents a possible target for antiinflammatory therapies.