RESUMEN
OBJECTIVE: Pediatric obsessive-compulsive disorder (OCD) sometimes appears rapidly, even overnight, often after an infection. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or PANDAS, describes such a situation after infection with Streptococcus pyogenes. PANDAS may result from induced autoimmunity against brain antigens, although this remains unproven. Pilot work suggests that IgG antibodies from children with PANDAS bind to cholinergic interneurons (CINs) in the striatum. CIN deficiency has been independently associated with tics in humans and with repetitive behavioral pathology in mice, making it a plausible locus of pathology. The authors sought to replicate and extend earlier work and to investigate the cellular effects of PANDAS antibodies on cholinergic interneurons. METHODS: Binding of IgG to specific neurons in human and mouse brain slices was evaluated ex vivo after incubation with serum from 27 children with rigorously characterized PANDAS, both at baseline and after intravenous immunoglobulin (IVIG) treatment, and 23 matched control subjects. Binding was correlated with symptom measures. Neural activity after serum incubation was assessed in mouse slices using molecular markers and electrophysiological recording. RESULTS: IgG from children with PANDAS bound to CINs, but not to several other neuron types, more than IgG from control subjects, in three independent cohorts of patients. Post-IVIG serum had reduced IgG binding to CINs, and this reduction correlated with symptom improvement. Baseline PANDAS sera decreased activity of striatal CINs, but not of parvalbumin-expressing GABAergic interneurons, and altered their electrophysiological responses, in acute mouse brain slices. Post-IVIG PANDAS sera and IgG-depleted baseline sera did not alter the activity of striatal CINs. CONCLUSIONS: These findings provide strong evidence for striatal CINs as a critical cellular target that may contribute to pathophysiology in children with rapid-onset OCD symptoms, and perhaps in other conditions.
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Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Neuronas Colinérgicas/inmunología , Cuerpo Estriado/inmunología , Trastorno Obsesivo Compulsivo/inmunología , Infecciones Estreptocócicas/inmunología , Animales , Enfermedades Autoinmunes/complicaciones , Estudios de Casos y Controles , Niño , Preescolar , Neuronas Colinérgicas/fisiología , Cuerpo Estriado/fisiopatología , Femenino , Humanos , Inmunoglobulina G/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Trastorno Obsesivo Compulsivo/complicaciones , Trastorno Obsesivo Compulsivo/etiología , Infecciones Estreptocócicas/complicacionesRESUMEN
BACKGROUND: Parasympathetic nerve hypersensitivity contributes to the severity of allergic rhinitis (AR), but the precise mechanism underlying neuroimmune regulation in patients with AR remains unclear. This study investigated the effect of cholinergic nerve inhibition on AR CD4+ T-helper (Th)2-cell polarization and the underlying regulatory mechanism in vitro. METHODS: An in-vitro neuroimmune coculture model of D-U87 cells and CD4+ T cells was established. D-U87 cells with cholinergic neuron characteristics were used as cholinergic neuron models. CD4+ T cells were derived from peripheral blood monocytes from AR patients (n = 60) and control subjects (n = 40). Th1- and Th2-cell percentages were measured by flow cytometry. Proteins involved in related signaling pathways were analyzed by protein chip assay and Western blotting. RESULTS: The Th2-cell percentage among CD4+ T cells from AR patients was significantly increased after coculture with D-U87 cells and was decreased by ipratropium bromide (IB) treatment. In contrast, the Th1-cell percentage among control CD4+ T cells was significantly increased after coculture with D-U87 cells, but was unaltered by IB treatment. Furthermore, phosphorylated Akt (p-Akt) protein levels increased in CD4+ T cells from both controls and AR patients after coculture with D-U87 cells and decreased after IB treatment. However, higher p-Akt levels were observed in cells from AR patients than in cells from control subjects. Moreover, Akt inhibition decreased Th2-cell percentage in AR patients. CONCLUSION: In-vitro cholinergic nerve inhibition with IB decreased AR CD4+ T-cell polarization into Th2 cells partially through an Akt-dependent mechanism.
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Linfocitos T CD4-Positivos/citología , Neuronas Colinérgicas/inmunología , Rinitis Alérgica/inmunología , Adolescente , Adulto , Línea Celular , Técnicas de Cocultivo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-akt/inmunología , Transducción de Señal , Adulto JovenRESUMEN
Basal forebrain cholinergic neurons mature in adolescence coinciding with development of adult cognitive function. Preclinical studies using the rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55) reveal persistent increases of brain neuroimmune genes that are associated with cognitive dysfunction. Adolescent intermittent ethanol exposure also reduces basal forebrain expression of choline acetyltransferase (ChAT), an enzyme critical for acetylcholine synthesis in cholinergic neurons similar to findings in the post-mortem human alcoholic basal forebrain. We report here that AIE decreases basal forebrain ChAT+IR neurons in both adult female and male Wistar rats following early or late adolescent ethanol exposure. In addition, we find reductions in ChAT+IR somal size as well as the expression of the high-affinity nerve growth factor (NGF) receptor tropomyosin receptor kinase A (TrkA) and the low-affinity NGF receptor p75NTR, both of which are expressed on cholinergic neurons. The decrease in cholinergic neuron marker expression was accompanied by increased phosphorylation of NF-κB p65 (pNF-κB p65) consistent with increased neuroimmune signaling. Voluntary wheel running from P24 to P80 prevented AIE-induced cholinergic neuron shrinkage and loss of cholinergic neuron markers (i.e., ChAT, TrkA, and p75NTR) as well as the increase of pNF-κB p65 in the adult basal forebrain. Administration of the anti-inflammatory drug indomethacin (4.0 mg/kg, i.p prior to each ethanol exposure) during AIE also prevented the loss of basal forebrain cholinergic markers and the concomitant increase of pNF-κB p65. In contrast, treatment with the proinflammatory immune activator lipopolysaccharide (1.0 mg/kg, i.p. on P70) caused a loss of cholinergic neuron markers that was paralleled by increased pNF-κB p65 in the basal forebrain. These novel findings are consistent with AIE causing lasting activation of the neuroimmune system that contributes to the persistent loss of basal forebrain cholinergic neurons in adulthood.
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Prosencéfalo Basal/efectos de los fármacos , Consumo Excesivo de Bebidas Alcohólicas/prevención & control , Terapia por Ejercicio , Indometacina/farmacología , Fármacos Neuroprotectores/farmacología , Consumo de Alcohol en Menores , Animales , Prosencéfalo Basal/crecimiento & desarrollo , Prosencéfalo Basal/inmunología , Prosencéfalo Basal/patología , Consumo Excesivo de Bebidas Alcohólicas/inmunología , Consumo Excesivo de Bebidas Alcohólicas/patología , Depresores del Sistema Nervioso Central/efectos adversos , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/inmunología , Neuronas Colinérgicas/patología , Modelos Animales de Enfermedad , Etanol/efectos adversos , Femenino , Masculino , Neuroinmunomodulación/efectos de los fármacos , Neuroinmunomodulación/fisiología , Distribución Aleatoria , Ratas Wistar , Carrera/fisiología , Maduración Sexual , VoliciónRESUMEN
Bifenthrin (BF) is a synthetic pyrethroid pesticide widely used in several countries to manage insect pests on diverse agricultural crops. Growing evidence indicates that BF exposure is associated with an increased risk of developing neurodegenerative disorders. However, the mechanisms by which BF induces neurological and anxiety alterations in the frontal cortex and striatum are not well known. The present in vivo study was carried out to determine whether reactive oxygen species (ROS)-mediated oxidative stress (OS) and neuroinflammation are involved in such alterations. Thirty-six Wistar rats were thus randomly divided into three groups and were orally administered with BF (0.6 and 2.1â¯mg/kg body weight, respectively) or the vehicle (corn oil), on a daily basis for 60 days. Results revealed that BF exposure in rats enhanced anxiety-like behavior after 60 days of treatment, as assessed with the elevated plus-maze test by decreases in the percentage of time spent in open arms and frequency of entries into these arms. BF-treated rats also exhibited increased oxidation of lipids and carbonylated proteins in the frontal cortex and striatum, and decreased glutathione levels and antioxidant enzyme activities including superoxide dismutase, catalase and glutathione peroxidase. Treatment with BF also increased protein synthesis and mRNA expression of the inflammatory mediators cyclooxygenase-2 (COX-2), microsomal prostaglandin synthase-1 (mPGES-1) and nuclear factor-kappaBp65 (NF-kBp65), as well as the production of tumor necrosis factor-α (TNF-α) and ROS. Moreover, BF exposure significantly decreased protein synthesis and mRNA expression of nuclear factor erythroid-2 (Nrf2) and acetylcholinesterase (AChE), as well as gene expression of muscarinic-cholinergic receptors (mAchR) and choline acetyltransferase (ChAT) in the frontal cortex and striatum. These data suggest that BF induced neurological alterations in the frontal cortex and striatum of rats, and that this may be associated with neuroinflammation and oxidative stress via the activation of Nrf2/NF-kBp65 pathways, which might promote anxiety-like behavior.
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Ansiedad/etiología , Insecticidas/toxicidad , Neuritis/inducido químicamente , Síndromes de Neurotoxicidad/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Piretrinas/toxicidad , Temblor/etiología , Animales , Conducta Animal/efectos de los fármacos , Biomarcadores/metabolismo , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/inmunología , Neuronas Colinérgicas/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/inmunología , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/inmunología , Lóbulo Frontal/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Insecticidas/administración & dosificación , Peroxidación de Lípido/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuritis/inmunología , Neuritis/metabolismo , Neuritis/fisiopatología , Síndromes de Neurotoxicidad/inmunología , Síndromes de Neurotoxicidad/metabolismo , Piretrinas/administración & dosificación , Distribución Aleatoria , Ratas WistarRESUMEN
Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus, or PANDAS, is a syndrome of acute childhood onset of obsessive-compulsive disorder and other neuropsychiatric symptoms in the aftermath of an infection with Group A beta-hemolytic Streptococcus (GABHS). Its pathophysiology remains unclear. PANDAS has been proposed to result from cross-reactivity of antibodies raised against GABHS with brain antigens, but the targets of these antibodies are unclear and may be heterogeneous. We developed an in vivo assay in mice to characterize the cellular targets of antibodies in serum from individuals with PANDAS. We focus on striatal interneurons, which have been implicated in the pathogenesis of tic disorders. Sera from children with well-characterized PANDAS (nâ¯=â¯5) from a previously described clinical trial (NCT01281969), and matched controls, were infused into the striatum of mice; antibody binding to interneurons was characterized using immunofluorescence and confocal microscopy. Antibodies from children with PANDAS bound to â¼80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. There was no elevated binding to two different populations of GABAergic interneurons (PV and nNOS-positive), confirming the specificity of this phenomenon. Elevated binding to cholinergic interneurons resolved in parallel with symptom improvement after treatment with intravenous immunoglobulin. Antibody-mediated dysregulation of striatal cholinergic interneurons may be a locus of pathology in PANDAS. Future clarification of the functional consequences of this specific binding may identify new opportunities for intervention in children with this condition.
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Anticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Neuronas Colinérgicas/inmunología , Cuerpo Estriado/inmunología , Interneuronas/inmunología , Infecciones Estreptocócicas/inmunología , Animales , Niño , Preescolar , Femenino , Humanos , Masculino , Ratones , Trastorno Obsesivo CompulsivoRESUMEN
Inflammation and other immune responses are involved in the variety of diseases and disorders. The acute response to endotoxemia includes activation of innate immune mechanisms as well as changes in autonomic nervous activity. The autonomic nervous system and the inflammatory response are intimately linked and sympathetic and vagal nerves are thought to have anti-inflammation functions. The basic functional circuit between vagus nerve and inflammatory response was identified and the neuroimmunomodulation loop was called cholinergic anti-inflammatory pathway. Unique function of vagus nerve in the anti-inflammatory reflex arc was found in many experimental and pre-clinical studies. They brought evidence on the cholinergic signaling interacting with systemic and local inflammation, particularly suppressing immune cells function. Pharmacological/electrical modulation of vagal activity suppressed TNF-alpha and other proinflammatory cytokines production and had beneficial therapeutic effects. Many questions related to mapping, linking and targeting of vagal-immune interactions have been elucidated and brought understanding of its basic physiology and provided the initial support for development of Tracey´s inflammatory reflex. This review summarizes and critically assesses the current knowledge defining cholinergic anti-inflammatory pathway with main focus on studies employing an experimental approach and emphasizes the potential of modulation of vagally-mediated anti-inflammatory pathway in the treatment strategies.
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Antiinflamatorios/inmunología , Neuronas Colinérgicas/inmunología , Neuroinmunomodulación/fisiología , Transducción de Señal/fisiología , Nervio Vago/inmunología , Animales , Antiinflamatorios/metabolismo , Colinérgicos/inmunología , Colinérgicos/metabolismo , Neuronas Colinérgicas/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Nervio Vago/metabolismoRESUMEN
The cholinergic anti-inflammatory pathway (CAP) is a complex neuroimmune mechanism triggered by the central nervous system to regulate peripheral inflammatory responses. Understanding the role of CAP in the pathogenesis of rheumatoid arthritis (RA) could help develop new therapeutic strategies for this disease. Therefore, we investigated the participation of this neuroimmune pathway on the progression of experimental arthritis. Using antigen-induced arthritis (AIA) model, we investigated in mice the effects of vagotomy or the pharmacological treatments with hexamethonium (peripheral nicotinic receptor antagonist), methylatropine (peripheral muscarinic receptor antagonist) or neostigmine (peripheral acetylcholinesterase inhibitor) on AIA progression. Unilateral cervical vagotomy was performed 1 week before the immunization protocol with methylated bovine serum albumin (mBSA), while drug administration was conducted during the period of immunization. On day 21, 6 hr after the challenge with mBSA injection in the femur-tibial joint, the local neutrophil migration and articular mechanical hyperalgesia were assessed. Herein, we observed that vagotomy or blockade of peripheral nicotinic (but not muscarinic) receptors exacerbated the clinical parameters of this disease. Moreover, peripheral acetylcholinesterase inhibition by neostigmine treatment promoted a reduction of neutrophil recruitment in the knee joint and articular hyperalgesia. Our results demonstrated that peripheral activation of CAP modulates experimental arthritis, providing a pre-clinical evidence of a potential therapeutic strategy for RA.
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Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Neuronas Colinérgicas/inmunología , Vías Eferentes/inmunología , Hiperalgesia/tratamiento farmacológico , Neuroinmunomodulación/efectos de los fármacos , Infiltración Neutrófila/efectos de los fármacos , Animales , Antígenos/efectos adversos , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/etiología , Artritis Reumatoide/tratamiento farmacológico , Derivados de Atropina/farmacología , Inhibidores de la Colinesterasa/farmacología , Hexametonio/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Antagonistas Muscarínicos/farmacología , Neostigmina/farmacología , Antagonistas Nicotínicos/farmacología , Albúmina Sérica Bovina , VagotomíaRESUMEN
Recent studies suggest that catecholamines (CAs) and acetylcholine (ACh) play essential roles in the crosstalk between microbes and the immune system. Host cholinergic afferent fibers sense pathogen-associated molecular patterns and trigger efferent cholinergic and catecholaminergic pathways that alter immune cell proliferation, differentiation, and cytokine production. On the other hand, microbes have the ability to produce and degrade ACh and also regulate autogenous functions in response to CAs. Understanding the role played by these neurotransmitters in host-microbe interactions may provide valuable information for the development of novel therapies.
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Acetilcolina/metabolismo , Sistema Nervioso Autónomo/inmunología , Sistema Nervioso Autónomo/microbiología , Catecolaminas/metabolismo , Neuronas Colinérgicas/inmunología , Animales , Enfermedades del Sistema Nervioso Autónomo/microbiología , Bacterias/inmunología , Diferenciación Celular/inmunología , Proliferación Celular , Colina O-Acetiltransferasa/metabolismo , Citocinas/biosíntesis , Interacciones Huésped-Patógeno/inmunología , Humanos , Macrófagos/inmunología , Neurotransmisores/metabolismo , Linfocitos T/inmunologíaRESUMEN
The cholinergic anti-inflammatory pathway controls innate immune responses and inflammation. The prostaglandin (PG) system is involved in several neuro-processes and associated with inflammatory activation of cells in vagal nuclei. Here we aimed to investigate the potential role of PG in cholinergic neuro-regulation. The effect of vagus nerve stimulation (VNS) has been evaluated in microsomal prostaglandin E synthase-1 (mPGES-1) knockout (-/-) and wild-type (+/+) mice regarding cytokine and PG levels after lipopolysaccharides (LPS) challenge. As expected, VNS decreased the release of pro-inflammatory cytokines both in serum and spleen extracts of mPGES-1 (+/+)animals. However, the immune suppressive effect of VNS was completely abolished in mPGES-1 (-/-) mice. The PG content was not affected by VNS in the spleen of mPGES-1 (+/+) and mPGES-1 (-/-) mice but interestingly, acetylcholine (ACh) release in spleen induced by VNS confirmed an intact cholinergic pathway in mPGES-1 (+/+) whereas no VNS-induced ACh release was found in mPGES-1 (-/-) animals. Our data show that mPGES-1 and consequently PGE2 are crucial in the cholinergic anti-inflammatory pathway. Moreover, the mechanisms involved do not affect PG content in the spleen, but lack of mPGES-1 was found to strongly affect cholinergic mechanisms in the inflamed spleen. These findings illustrate previously unrecognized associations between the cholinergic and prostaglandin systems, and may be of importance for further development of therapeutic strategies directed at modulation of the inflammatory reflex, and immunosuppression in chronic inflammatory diseases.
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Neuronas Colinérgicas/metabolismo , Dinoprostona/metabolismo , Endotoxemia/metabolismo , Oxidorreductasas Intramoleculares/metabolismo , Microsomas/enzimología , Neuroinmunomodulación , Bazo/enzimología , Acetilcolina/metabolismo , Animales , Encéfalo/enzimología , Encéfalo/inmunología , Encéfalo/metabolismo , Neuronas Colinérgicas/inmunología , Citocinas/sangre , Citocinas/metabolismo , Endotoxemia/inmunología , Endotoxemia/fisiopatología , Endotoxemia/terapia , Inmunidad Innata , Terapia de Inmunosupresión , Oxidorreductasas Intramoleculares/genética , Lipopolisacáridos/toxicidad , Ratones Congénicos , Ratones Noqueados , Microsomas/inmunología , Microsomas/metabolismo , Prostaglandina-E Sintasas , Bazo/inmunología , Bazo/inervación , Bazo/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Síndrome de Respuesta Inflamatoria Sistémica/prevención & control , Nervio Vago/inmunología , Nervio Vago/metabolismo , Nervio Vago/fisiopatología , Enfermedades del Nervio Vago/etiología , Enfermedades del Nervio Vago/prevención & control , Estimulación del Nervio VagoRESUMEN
Glucagon is a hyperglycemic pancreatic hormone that has been shown to provide a beneficial effect against asthmatic bronchospasm. We investigated the role of this hormone on airway smooth muscle contraction and lung inflammation using both in vitro and in vivo approaches. The action of glucagon on mouse cholinergic tracheal contraction was studied in a conventional organ bath system, and its effect on airway obstruction was also investigated using the whole-body pletysmographic technique in mice. We also tested the effect of glucagon on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and inflammation. The expression of glucagon receptor (GcgR), CREB, phospho-CREB, nitric oxide synthase (NOS)-3, pNOS-3 and cyclooxygenase (COX)-1 was evaluated by western blot, while prostaglandin E2 (PGE2) and tumour necrosis factor-α were quantified by enzyme-linked immunoassay and ELISA respectively. Glucagon partially inhibited carbachol-induced tracheal contraction in a mechanism clearly sensitive to des-His1-[Glu9]-glucagon amide, a GcgR antagonist. Remarkably, GcgR was more expressed in the lung and trachea with intact epithelium than in the epithelium-denuded trachea. In addition, the glucagon-mediated impairment of carbachol-induced contraction was prevented by either removing epithelial cells or blocking NOS (L-NAME), COX (indomethacin) or COX-1 (SC-560). In contrast, inhibitors of either heme oxygenase or COX-2 were inactive. Intranasal instillation of glucagon inhibited methacholine-induced airway obstruction by a mechanism sensitive to pretreatment with L-NAME, indomethacin and SC-560. Glucagon induced CREB and NOS-3 phosphorylation and increased PGE2 levels in the lung tissue without altering COX-1 expression. Glucagon also inhibited LPS-induced AHR and bronchoalveolar inflammation. These findings suggest that glucagon possesses airway-relaxing properties that are mediated by epithelium-NOS-3-NO- and COX-1-PGE2-dependent mechanisms.
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Broncodilatadores/farmacología , Neuronas Colinérgicas/efectos de los fármacos , Dinoprostona/metabolismo , Glucagón/farmacología , Músculo Liso/efectos de los fármacos , Óxido Nítrico/metabolismo , Tráquea/efectos de los fármacos , Administración Intranasal , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Asma/tratamiento farmacológico , Asma/inmunología , Asma/metabolismo , Hiperreactividad Bronquial/tratamiento farmacológico , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Broncodilatadores/administración & dosificación , Broncodilatadores/uso terapéutico , Neuronas Colinérgicas/inmunología , Neuronas Colinérgicas/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Glucagón/administración & dosificación , Glucagón/uso terapéutico , Técnicas In Vitro , Masculino , Ratones Endogámicos A , Relajación Muscular/efectos de los fármacos , Músculo Liso/inmunología , Músculo Liso/inervación , Músculo Liso/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Tráquea/inmunología , Tráquea/inervación , Tráquea/metabolismoRESUMEN
The nervous and immune systems are likely to be interacting in arthritis, with the possible involvement of both neural and non-neural cholinergic transmission. Centrally acting muscarinic agonists, electrical stimulation of the vagus and treatment with nicotinic receptor agonists can all act systemically to reduce inflammation, although the responsible pathways are incompletely understood. While this 'cholinergic anti-inflammatory pathway' is widely viewed as a significant pathophysiological mechanism controlling inflammation, the evidence supporting this view is critically reviewed and considered inconclusive; an alternative pathway via sympathetic nerves is implicated. This review also discusses how cholinergic pathways, both neural and non-neural, may impact on inflammation and specifically arthritis. Nicotinic agonists have been reported to reduce the incidence and severity of murine arthritis, albeit an observation we could not confirm, and clinical studies in rheumatoid arthritis have been proposed and/or are underway. While the therapeutic potential of nicotinic agonists and vagal stimulation is clear, we suggest that the 'cholinergic anti-inflammatory pathway' should not be uncritically embraced as a significant factor in the pathogenesis of rheumatoid arthritis.
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Artritis Reumatoide/inmunología , Artritis Reumatoide/fisiopatología , Neuronas Colinérgicas/inmunología , Inflamación/inmunología , Animales , Vías Autónomas/fisiología , Colinérgicos/inmunología , Fibras Colinérgicas/inmunología , Fibras Colinérgicas/fisiología , Neuronas Colinérgicas/fisiología , Progresión de la Enfermedad , Femenino , Humanos , Sistema Inmunológico/metabolismo , Sistema Inmunológico/fisiopatología , Inflamación/fisiopatología , Masculino , Ratones , Receptores Colinérgicos/efectos de los fármacos , Sensibilidad y EspecificidadRESUMEN
The prevalence of food allergy (FA) has increased in developed countries over the past few decades. However, no effective drug therapies are currently available. Therefore, we investigated cholinergic anti-inflammatory pathway as a regulatory system to ameliorate disrupted mucosal immune homeostasis in the gut based on the pathophysiological elucidation of mucosal mast cells (MMCs) in a murine FA model. BALB/c mice sensitized with ovalbumin received repeated oral ovalbumin for the development of FA. FA mice developed severe allergic diarrhea and exhibited enhanced type 2 helper T (Th2) cell immune responses in both systemic immunity and mucosal immunity, along with MMCs hyperplasia in the colon. MMCs were localized primarily in the strategic position of the mucosal epithelium. Furthermore, the allergic symptoms did not develop in p85α disrupted phosphoinositide-3 kinase-deficient mice that lacked mast cells in the gut. Vagal stimulation by 2-deoxy-D-glucose and drug treatment with nicotinic ACh receptor (nAChR) agonists (nicotine and α7 nAChR agonist GTS-21) alleviated the allergic symptoms in the FA mice. Nicotine treatment suppressed MMCs hyperplasia, enhanced MPO and upregulated mRNA expression of Th1 and Th2 cytokines in the FA mice colon. MMCs, which are negatively regulated by α7 nAChRs, were often located in close proximity to cholinergic CGRP-immunoreactive nerve fibers in the FA mice colon. The present results reveal that the cholinergic neuroimmune interaction via α7 nAChRs on MMCs is largely involved in maintaining intestinal immune homeostasis and can be a target for a new therapy against mucosal immune diseases with homeostatic disturbances such as FA.
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Neuronas Colinérgicas/inmunología , Hipersensibilidad a los Alimentos/inmunología , Mucosa Intestinal/inmunología , Mastocitos/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/fisiología , Animales , Colon/inmunología , Colon/inervación , Colon/patología , Hipersensibilidad a los Alimentos/metabolismo , Mucosa Intestinal/patología , Masculino , Mastocitos/inmunología , Mastocitos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Ratones Transgénicos , Células Th2/inmunología , Nervio Vago/patología , Nervio Vago/fisiopatologíaRESUMEN
BACKGROUND AND PURPOSE: Emerging evidence indicates that the balance between pro-inflammatory cytokines (PICs) and anti-inflammatory cytokines (AICs) within the brain is an important determinant in the outcome of hypertension. However, the mechanism by which this dysregulation occurs is not known. We aimed to investigate whether AngII induces imbalance between PIC and AIC by modulating downstream transcription factors, NFκB and cyclic AMP response element-binding protein (CREB), and whether AngII-induced effects are mediated by glycogen synthase kinase-3ß (GSK-3ß). EXPERIMENTAL APPROACH: CATH.a neurons were exposed to AngII (10 nM-1 µM) over a preset time course. In another set of experiments, GSK-3ß was knock down by using lentivirus containing short hairpin RNA targeting GSK-3ß (L-sh-GSK3ß) before AngII exposure. Cell extracts were subjected to RT-PCR, immunoblot and immunoprecipitation. KEY RESULTS: AngII caused time-dependent increase in PICs (TNF-α and IL-1ß) and reduction in AIC (IL-10). AngII exposure caused reduced phosphorylated CREB(Ser-133) and increased p-NFκB(Ser-276) levels, leading to reduced CREB-CBP and increased NFκB-CBP binding. These results were accompanied by increased activation of GSK-3ß, as indicated by increased p-GSK3(Tyr-216) to p-GSK3(Ser-9) ratio. In a subsequent study, pretreatment with L-sh-GSK3ß attenuated AngII-induced alterations in PICs and IL-10 by augmenting CREB-CBP and attenuating NFκB-CBP binding. CONCLUSIONS AND IMPLICATIONS: Collectively, these findings are the first to provide direct evidence that AngII-induced dysregulation in cytokines is mediated by GSK-3ß-mediated alterations in downstream transcription factors in neuronal cells. Our data also reveal that AngII-induced effects could be alleviated by GSK-3ß inhibition, suggesting GSK-3ß as an important therapeutic target for hypertension that is characterized by increased PICs and NFκB activation.