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Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2. These results may explain proinflammatory cytokine release via the associated angiotestin II pathway and a possible therapeutic target via the IL-6-STAT3 axis.
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Quirópteros , Coronavirus , Animales , Betacoronavirus , COVID-19 , Infecciones por Coronavirus , Síndrome de Liberación de Citoquinas , Pandemias , Neumonía Viral , SARS-CoV-2 , Internalización del VirusRESUMEN
Since the molecular cloning of interleukin-6 (IL-6) in 1986, many other cytokines have been found to share the same signal transducer, gp130, in their receptor complexes. Thus, the IL-6 family of cytokines now consists of ten members. Although some of the family members' functions are redundant as a result of the expression of gp130, there are also functional distinctions between members. The mechanisms that determine functional redundancies and distinctions are not completely understood. Yet, research has clarified the role of IL-6 family cytokines in autoimmune diseases and has led to effective therapies that target them. Here, we review the IL-6 family of cytokines in autoimmune diseases, with a particular focus on the prototypical member IL-6, from the viewpoints of their structure, signaling, and biological features and discuss possible mechanisms of their functional pleiotropy.
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Citocinas/fisiología , Pleiotropía Genética , Familia de Multigenes/fisiología , Animales , Enfermedades Autoinmunes/inmunología , Citocinas/genética , Regulación de la Expresión Génica , Inflamación/inmunología , Interleucina-6/antagonistas & inhibidores , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-6/fisiología , Ratones , Subunidades de Proteína , Receptores de Citocinas/fisiología , Receptores de Interleucina-6/fisiología , Transducción de Señal , Relación Estructura-ActividadRESUMEN
Although it is believed that neural activation can affect immune responses, very little is known about the neuroimmune interactions involved, especially the regulators of immune traffic across the blood-brain barrier which occurs in neuroimmune diseases such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis, we show that autoreactive T cells access the central nervous system via the fifth lumbar spinal cord. This location is defined by IL-6 amplifier-dependent upregulation of the chemokine CCL20 in associated dorsal blood vessels, which in turn depends on gravity-induced activation of sensory neurons by the soleus muscle in the leg. Impairing soleus muscle contraction by tail suspension is sufficient to reduce localized chemokine expression and block entry of pathogenic T cells at the fifth lumbar cord, suggesting that regional neuroimmune interactions may offer therapeutic targets for a variety of neurological diseases.
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Barrera Hematoencefálica , Linfocitos T CD4-Positivos/citología , Encefalomielitis Autoinmune Experimental/inmunología , Animales , Movimiento Celular , Quimiocina CCL20/inmunología , Encefalomielitis Autoinmune Experimental/patología , Gravitación , Interleucina-6/inmunología , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Músculo Esquelético/inervación , Neuroinmunomodulación , Médula Espinal/irrigación sanguíneaRESUMEN
Calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis is standard in allogeneic hematopoietic stem cell transplantation (HCT) but fails to induce long-term tolerance without chronic GVHD (cGVHD) in a considerable number of patients. In this study, we addressed this long-standing question in mouse models of HCT. After HCT, alloreactive donor T cells rapidly differentiated into PD-1+ TIGIT+ terminally exhausted T cells (terminal Tex). GVHD prophylaxis with cyclosporine (CSP) suppressed donor T-cell expression of TOX, a master regulator to promote differentiation of transitory exhausted T cells (transitory Tex), expressing both inhibitory receptors and effector molecules, into terminal Tex, and inhibited tolerance induction. Adoptive transfer of transitory Tex, but not terminal Tex, into secondary recipients developed cGVHD. Transitory Tex maintained alloreactivity and thus PD-1 blockade restored graft-versus-leukemia (GVL) activity of transitory Tex and not terminal Tex. In conclusion, CSP inhibits tolerance induction by suppressing the terminal exhaustion of donor T cells, while maintaining GVL effects to suppress leukemia relapse.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia , Ratones , Animales , Inhibidores de la Calcineurina/farmacología , Linfocitos T , Enfermedad Injerto contra Huésped/prevención & control , Receptor de Muerte Celular Programada 1 , Ciclosporina/farmacología , Tolerancia InmunológicaRESUMEN
We recently discovered a (to our knowledge) new neuroimmune interaction named the gateway reflex, in which the activation of specific neural circuits establishes immune cell gateways at specific vessel sites in organs, leading to the development of tissue-specific autoimmune diseases, including a multiple sclerosis (MS) mouse model, experimental autoimmune encephalomyelitis (EAE). We have reported that peripheral-derived myeloid cells, which are CD11b+MHC class II+ and accumulate in the fifth lumbar (L5) cord during the onset of a transfer model of EAE (tEAE), play a role in the pain-mediated relapse via the pain-gateway reflex. In this study, we investigated how these cells survive during the remission phase to cause the relapse. We show that peripheral-derived myeloid cells accumulated in the L5 cord after tEAE induction and survive more than other immune cells. These myeloid cells, which highly expressed GM-CSFRα with common ß chain molecules, grew in number and expressed more Bcl-xL after GM-CSF treatment but decreased in number by blockade of the GM-CSF pathway, which suppressed pain-mediated relapse of neuroinflammation. Therefore, GM-CSF is a survival factor for these cells. Moreover, these cells were colocalized with blood endothelial cells (BECs) around the L5 cord, and BECs expressed a high level of GM-CSF. Thus, GM-CSF from BECs may have an important role in the pain-mediated tEAE relapse caused by peripheral-derived myeloid cells in the CNS. Finally, we found that blockade of the GM-CSF pathway after pain induction suppressed EAE development. Therefore, GM-CSF suppression is a possible therapeutic approach in inflammatory CNS diseases with relapse, such as MS.
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Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Ratones , Animales , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Enfermedades Neuroinflamatorias , Células Endoteliales/metabolismo , Sistema Nervioso Central , Dolor/metabolismo , Células Mieloides , RecurrenciaRESUMEN
The IL-6 amplifier was originally discovered as a mechanism for the enhanced activation of NF-κB in non-immune cells. In the IL-6 amplifier, IL-6-STAT3 and NF-κB stimulation is followed by an excessive production of IL-6, chemokines, and growth factors to develop chronic inflammation preceding the development of inflammatory diseases. Previously, using a shRNA-mediated genome-wide screening, we found that DEAD-Box Helicase 6 (DDX6) is a candidate positive regulator of the amplifier. Here, we investigate whether DDX6 is involved in the pathogenesis of inflammatory diseases via the IL-6 amplifier. We found that DDX6-silencing in non-immune cells suppressed the NF-κB pathway and inhibited activation of the IL-6 amplifier, while the forced expression of DDX6 enhanced NF-κB promoter activity independent of the RNA helicase activity of DDX6. The imiquimod-mediated dermatitis model was suppressed by the siRNA-mediated gene downregulation of DDX6. Furthermore, silencing DDX6 significantly reduced the TNF-α-induced phosphorylation of p65/RelA and IκBα, nuclear localization of p65, and the protein levels of IκBα. Mechanistically, DDX6 is strongly associated with p65 and IκBα, but not TRADD, RIP, or TRAF2, suggesting a novel function of DDX6 as an adaptor protein in the NF-κB pathway. Thus, our findings demonstrate a possible role of DDX6 beyond RNA metabolism and suggest DDX6 is a therapeutic target for inflammatory diseases.
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ARN Helicasas DEAD-box , FN-kappa B , Regulación de la Expresión Génica , Interleucina-6/metabolismo , FN-kappa B/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Transducción de Señal , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , ARN Helicasas DEAD-box/metabolismoRESUMEN
BACKGROUND: Maintaining an adequate temperature at the target site is essential for effective ablation. We hypothesized that a tissue temperature-controlled (T-Con) catheter for cavotricuspid isthmus (CTI) ablation could improve the procedural ablation parameters. PURPOSE: To evaluate the efficacy and safety of the T-Con (DiamondTemp™) catheter for CTI ablation compared with non-irrigation (Non-Irri) and irrigation (Irri) catheters. METHODS: We analyzed 150 patients who underwent prophylactic CTI ablation combined with pulmonary vein isolation. The Non-Irri, Irri, and T-Con catheter groups comprised 50 patients each, and the ablation procedural parameters and complications were compared between these groups. RESULTS: There were no significant differences in clinical background characteristics among the three groups. The Kruskal-Wallis and post hoc tests demonstrated that the T-Con group showed the lowest total radiofrequency energy delivery time among the three groups (median [25 and 75 percentiles]: 340 [209, 357], 147 [100, 199], and 83 [61, 109] s, respectively in the Non-Irri, Irri, and T-Con groups; T-Con versus Non-Irri, p < .01; T-Con versus Irri, p < .01). The total procedural time and acute reconnection rate in the T-Con group (264 s and 4%, respectively) were lower than those in the Non-Irri group (438 s and 24%) but were similar to those in the Irri group (268 s and 6%). No significant complications were observed in any group. CONCLUSIONS: The T-Con catheter achieved a short energy delivery time and a low acute reconnection rate, indicating its potential as an alternative catheter for CTI ablation.
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OBJECTIVE: In hemodialysis patients with a difficult access extremity who are not suitable for an arteriovenous fistula or arteriovenous graft creation, the concept of cannulating a superficialized artery for arterial outflow in dialysis sessions has been adopted as a tertiary alternative. However, its long-term patency and complications have not been recognized widely. We report our 16-year experience with hemodialysis access creation using the brachial artery transposition (BAT) technique. METHODS: This single-center retrospective study included consecutive patients who underwent BAT for hemodialysis vascular access between June 1, 2006, and December 31, 2022. The patency of the whole access circuit and the transposed brachial artery itself was evaluated independently. RESULTS: In total, 193 surgical procedures were included. The success rate was 93.2%. The mean operative time was 128 minutes. The median interval from access placement to first cannulation was 21 days. The primary patency rates for BAT were 92.3%, 91.3%, 90.3%, 86.1%, and 71.9% at 1, 2, 3, 5, and 10 years, respectively. The secondary patency rates for BAT were 96.3%, 96.3%, 95.0%, 90.1%, and 74.9% at 1, 2, 3, 5, and 10 years, respectively. The primary patency rates for the whole access circuit were 61.4%, 49.2%, 45.8%, and 26.9% at 1, 2, 3, and 5 years, respectively. The secondary patency rates for the whole access circuit were 85.1%, 83.3%, 82.0%, and 68.6% at 1, 2, 3, and 5 years, respectively. The overall patient survival rates were 79.6%, 69.6%, 54.6%, 36.5%, and 13.4% at 1, 2, 3, 5 and 10 years, respectively. The abandonments of BAT were brachial artery thrombosis (n = 6), pseudoaneurysm (n = 2), aneurysmal change (n = 1), and other reasons (n = 1). The abandonments of the whole access circuit were exhaustion of venous return (n = 26), abandonment of BAT (n = 7), and other reasons (n = 2). Complications were exhaustion of venous return (n = 26), aneurysmal change (n = 12), pseudoaneurysm (n = 6), brachial artery thrombosis (n = 7), impaired wound healing (n = 19), lymphorrhea (n = 9), skin infection (n = 5), hematoma on cannulation (n = 3), and reduced peripheral blood flow (n = 2). CONCLUSIONS: The patency of BAT was excellent, and that of the whole access circuit was adequate, with a few complications. BAT is an effective alternative from a long-term perspective for patients who are unsuitable for conventional hemodialysis access creation.
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Arteria Braquial , Diálisis Renal , Grado de Desobstrucción Vascular , Humanos , Arteria Braquial/cirugía , Arteria Braquial/fisiopatología , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , Anciano , Factores de Tiempo , Factores de Riesgo , Extremidad Superior/irrigación sanguínea , Derivación Arteriovenosa Quirúrgica/efectos adversos , Adulto , Anciano de 80 o más Años , Oclusión de Injerto Vascular/etiología , Oclusión de Injerto Vascular/fisiopatologíaRESUMEN
The interleukin-6 (IL-6) amplifier, which describes the simultaneous activation of signal transducer and activator of transcription 3 (STAT3) and NF-κb nuclear factor kappa B (NF-κB), in synovial fibroblasts causes the infiltration of immune cells into the joints of F759 mice. The result is a disease that resembles human rheumatoid arthritis. However, the kinetics and regulatory mechanisms of how augmented transcriptional activation by STAT3 and NF-κB leads to F759 arthritis is unknown. We here show that the STAT3-NF-κB complex is present in the cytoplasm and nucleus and accumulates around NF-κB binding sites of the IL-6 promoter region and established a computer model that shows IL-6 and IL-17 (interleukin 17) signaling promotes the formation of the STAT3-NF-κB complex followed by its binding on promoter regions of NF-κB target genes to accelerate inflammatory responses, including the production of IL-6, epiregulin, and C-C motif chemokine ligand 2 (CCL2), phenotypes consistent with in vitro experiments. The binding also promoted cell growth in the synovium and the recruitment of T helper 17 (Th17) cells and macrophages in the joints. Anti-IL-6 blocking antibody treatment inhibited inflammatory responses even at the late phase, but anti-IL-17 and anti-TNFα antibodies did not. However, anti-IL-17 antibody at the early phase showed inhibitory effects, suggesting that the IL-6 amplifier is dependent on IL-6 and IL-17 stimulation at the early phase, but only on IL-6 at the late phase. These findings demonstrate the molecular mechanism of F759 arthritis can be recapitulated in silico and identify a possible therapeutic strategy for IL-6 amplifier-dependent chronic inflammatory diseases.
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Artritis Reumatoide , Interleucina-6 , Humanos , Animales , Ratones , Interleucina-6/metabolismo , FN-kappa B/metabolismo , Membrana Sinovial/metabolismo , Simulación por Computador , Fibroblastos/metabolismoRESUMEN
Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two single nucleotide polymorphisms (SNPs) associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and ßTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC.
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Contractura de Dupuytren , Humanos , Contractura de Dupuytren/genética , Contractura de Dupuytren/patología , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma Completo , FN-kappa B/metabolismo , Interleucina-6/metabolismo , Fibroblastos/metabolismo , Inflamación/genética , Inflamación/metabolismo , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
Using a zoobiquity concept, we directly connect animal phenotypes to a human disease mechanism: the reduction of local plasminogen levels caused by matrix metalloproteinase-9 (MMP9) activity is associated with the development of inflammation in the intestines of dogs and patients with inflammatory bowel disease. We first investigated inflammatory colorectal polyps (ICRPs), which are a canine gastrointestinal disease characterized by the presence of idiopathic chronic inflammation, in Miniature Dachshund (MD) and found 31 missense disease-associated SNPs by whole-exome sequencing. We sequenced them in 10 other dog breeds and found five, PLG, TCOF1, TG, COL9A2 and COL4A4, only in MD. We then investigated two rare and breed-specific missense SNPs (T/T SNPs), PLG: c.477G > T and c.478A>T, and found that ICRPs with the T/T SNP risk alleles showed less intact plasminogen and plasmin activity in the lesions compared to ICRPs without the risk alleles but no differences in serum. Moreover, we show that MMP9, which is an NF-κB target, caused the plasminogen reduction and that intestinal epithelial cells expressing plasminogen molecules were co-localized with epithelial cells expressing MMP9 in normal colons with the risk alleles. Importantly, MMP9 expression in patients with ulcerous colitis or Crohn's disease also co-localized with epithelial cells showing enhanced NF-κB activation and less plasminogen expression. Overall, our zoobiquity experiments showed that MMP9 induces the plasminogen reduction in the intestine, contributing to the development of local inflammation and suggesting the local MMP9-plasminogen axis is a therapeutic target in both dogs and patients. Therefore, zoobiquity-type experiments could bring new perspectives for biomarkers and therapeutic targets.
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Enfermedades Inflamatorias del Intestino , Metaloproteinasa 9 de la Matriz , Humanos , Perros , Animales , Plasminógeno , FN-kappa B , Inflamación , Serina ProteasasRESUMEN
INTRODUCTION: Various adjunctive approaches to pulmonary vein isolation (PVI) have been attempted for persistent atrial fibrillation (perAF) and longstanding persistent AF (ls-perAF). We aimed to identify the novel zones responsible for perpetuation of AF. METHODS: To identify novel zones acting as a source of perAF and ls-perAF after PVI/re-PVI, we performed fractionation mapping in 258 consecutive patients with perAF (n = 207) and ls-perAF (n = 51) in whom PVI/re-PVI failed to restore sinus rhythm. RESULTS: In 15 patients with perAF (5.8%: 15/258), fractionation mapping identified a small solitary zone (<1 cm2 ) with high-frequency and irregular waves, showing fractionated electrograms (EGM). We defined this zone as the small solitary atrial fractionated EGM (SAFE) zone. The small SAFE zone was surrounded characteristically by a homogeneous area showing relatively organized activation with nonrapid and nonfractionated waves. Only one small SAFE zone was detected in each patient. This characteristic electrical phenomenon was observed stably during the procedure until ablation. AF duration, (defined as the duration between initial detection of AF and the current ablation) was longer in patients with the small SAFE zone than in those without (median, [25 and 75 percentiles]; 5.0 [3.5, 7.0] vs. 1.1 [1.0, 4.0] years, p = .0008). Longer AF cycle length was observed in patients with the small SAFE zone than in those without. The ablation of the small SAFE zone terminated AF in all 15 patients without any need for other ablations. AF/atrial tachycardia-free rate at follow-up was 93% (14/15) at 6 months, 87% (13/15) at 1 year, and 60% (9/15) at 2 years. CONCLUSIONS: Using fractionation mapping, this study identified a small SAFE zone surrounded characteristically by a homogeneous, relatively organized, low-excitability EGM lesion. The ablation of the small SAFE zone terminated AF in all patients, demonstrating it as a substrate for perpetuated AF. Our findings provide novel ablation targets in perAF patients with prolonged AF duration. Further studies to confirm the present results are warranted.
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Fibrilación Atrial , Ablación por Catéter , Venas Pulmonares , Humanos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/cirugía , Resultado del Tratamiento , Ablación por Catéter/efectos adversos , Ablación por Catéter/métodos , Técnicas Electrofisiológicas Cardíacas , Venas Pulmonares/cirugía , RecurrenciaRESUMEN
Gateway reflexes are neural circuits that maintain homeostasis of the immune system. They form gateways for autoreactive T cells to infiltrate the central nervous system in a noradrenaline-dependent manner despite the blood-brain barrier. This mechanism is critical not only for maintaining organ homeostasis but also for inflammatory disease development. Gateway reflexes can be regulated by environmental or artificial stimuli including electrical stimulation, suggesting that the infiltration of immune cells can be controlled by bioelectronic medicine. In this review, we describe the discovery of gateway reflexes and their future directions with special focus on bioelectronic medicine.
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Sistema Nervioso Central , Linfocitos T , Barrera Hematoencefálica , Neuronas , NorepinefrinaRESUMEN
Multicentric Castleman disease-thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly (MCD-TAFRO)-is an emergent phenotype characterized by lymphoproliferation, fluid collection, hemocytopenia and multiple organopathy. Although studies have demonstrated an aberrant blood cytokine/chemokine profile referred to as "chemokine storm", the pathogenesis remains unclear. We aimed to identify pathogenic key molecules, potential diagnostic targets and therapeutic markers in MCD-TAFRO using serum cytokine/chemokine profiles. We performed the targeted cytokine/chemokine multiplex analysis in six cases of MCD-TAFRO with remission or non-remission status. We observed significant changes in serum concentrations of CCL2, CCL5, and Chitinase-3-like-1 in the MCD-TAFRO patients with active state compared to inactive state. Ingenuity pathway analysis revealed that glycogen synthase kinase 3 (GSK3) and CCR6, which is expressed in megakaryocytes, were detected as upstream positive regulators for activating MCD-TAFRO status. More GSK3ß+ CCR6+ cells like megakaryocytes were detected in the bone marrow of patients with MCD-TAFRO than in those with systemic lupus erythematosus, MCD-not otherwise specified or autoimmune haemophagocytic lymphohistiocytosis. The cellularity of GSK3ß+ CCR6+ cells was correlated with disease activity, including thrombocytopenia and anaemia. In conclusion, GSK3ß and CCR6 of bone marrow cells were potentially involved in the pathogenesis of MCD-TAFRO and may act as diagnostic targets and therapeutic markers.
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Médula Ósea/patología , Enfermedad de Castleman/patología , Glucógeno Sintasa Quinasa 3 beta/análisis , Receptores CCR6/análisis , Adulto , Anciano , Enfermedad de Castleman/complicaciones , Femenino , Humanos , Inflamación/complicaciones , Inflamación/patología , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients' data. METHODS: Sleep disturbance stress (SDS) for 2 weeks was placed on 6-8-week-old female MRL/lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE. RESULTS: SDS-subjected MRL/lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/lpr. A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b. We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE. CONCLUSIONS: The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE.
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Lupus Eritematoso Sistémico , Microglía , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Interleucina-12 , Subunidad p19 de la Interleucina-23/metabolismo , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ratones , Ratones Endogámicos MRL lpr , Microglía/metabolismo , Estrés Fisiológico , TYK2 QuinasaRESUMEN
We have been studying inflammatory diseases, with a special focus on IL-6, and discovered two concepts related to inflammation development. One is the gateway reflex, which is induced by the activation of specific neural circuits followed by establishing gateways for autoreactive CD4+ T cells to pass through blood barriers toward the central nervous system (CNS) and retina during tissue-specific inflammatory diseases. We found that the formation of these gateways is dependent on the IL-6 amplifier, which is machinery for enhanced NF-κB activation in endothelial cells at specific sites. We have found five gateway reflexes in total. Here, we introduce the gateway reflex and the IL-6 amplifier.
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Células Endoteliales/inmunología , Inflamación/inmunología , Interleucina-6/inmunología , FN-kappa B/inmunología , Animales , Sistema Nervioso Central/inmunología , HumanosRESUMEN
Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammation with lymphoid infiltration and destruction of the salivary glands. Although many genome-wide association studies have revealed disease-associated risk alleles, the functions of the majority of these alleles are unclear. Here, we show previously unrecognized roles of GTF2I molecules by using two SS-associated single nucleotide polymorphisms (SNPs), rs73366469 and rs117026326 (GTF2I SNPs). We found that the risk alleles of GTF2I SNPs increased GTF2I expression and enhanced nuclear factor-kappa B (NF-κB) activation in human salivary gland cells via the NF-κB p65 subunit. Indeed, the knockdown of GTF2I suppressed inflammatory responses in mouse endothelial cells and in vivo. Conversely, the over-expression of GTF2I enhanced NF-κB reporter activity depending on its p65-binding N-terminal leucine zipper domain. GTF2I is highly expressed in the human salivary gland cells of SS patients expressing the risk alleles. Consistently, the risk alleles of GTF2I SNPs were strongly associated with activation of the IL-6 amplifier, which is hyperactivation machinery of the NF-κB pathway, and lymphoid infiltration in the salivary glands of SS patients. These results demonstrated that GTF2I expression in salivary glands is increased in the presence of the risk alleles of GTF2I SNPs, resulting in activation of the NF-κB pathway in salivary gland cells. They also suggest that GTF2I could be a new therapeutic target for SS.
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Inflamación/genética , Polimorfismo de Nucleótido Simple/genética , Glándulas Salivales/patología , Síndrome de Sjögren/genética , Factores de Transcripción TFII/genética , Adulto , Anciano , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Células Cultivadas , Células Endoteliales/patología , Células Epiteliales/patología , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , FN-kappa B/genética , Transducción de Señal/genéticaRESUMEN
Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5'-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5'-terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor ß (PDGFRß) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, eIF4A/4E-dependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among eIF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands.
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Factores de Ribosilacion-ADP/metabolismo , Antígeno B7-H1/metabolismo , Evasión Inmune/genética , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/genética , Factor 6 de Ribosilación del ADP , Sitios de Unión , Biomarcadores de Tumor , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Modelos Moleculares , Mutación , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Unión Proteica , ARN Mensajero/genética , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de SeñalRESUMEN
The immune and nervous systems share many features, including receptor and ligand expression, enabling efficient communication between the two. Accumulating evidence suggests that the communication is bidirectional, with the neural system regulating immune cell functions and vice versa. Steroid hormones from the hypothalamus-pituitary-adrenal gland axis are examples of systemic regulators for this communication. Neural reflexes describe regional regulation mechanisms that are a historically new concept that helps to explain how the neural and body systems including immune system communicate. Several recently identified neural reflexes, including the inflammatory reflex and gateway reflex, significantly impact the activation status of the immune system and are associated with inflammatory diseases and disorders. Either pro-inflammatory or anti-inflammatory effects can be elicited by these neural reflexes. On the other hand, the activities of immune cells during inflammation, for example the secretion of inflammatory mediators, can affect the functions of neuronal systems via neural reflexes and modulate biological outputs via specific neural pathways. In this review article, we discuss recent advances in the understanding of bidirectional neuro-immune interactions, with a particular focus on neural reflexes.
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Sistema Inmunológico/inmunología , Neuroinmunomodulación/inmunología , Neuronas/inmunología , Animales , HumanosRESUMEN
Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1-enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.