RESUMEN
Early-life stress (ELS) is a high-risk factor for the development of chronic visceral pain in adulthood. Emerging evidence suggests that mast cells play a key role in the development of visceral hypersensitivity through interaction with neurons. The sensitization of corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the pathogenesis of visceral pain. However, the precise mechanism by which mast cells and CRF neurons interact in the PVN in the pathogenesis of visceral hypersensitivity remains elusive. In the present study, we used neonatal maternal separation (MS), an ELS model, and observed that neonatal MS induced visceral hypersensitivity and triggered PVN mast cell activation in adult rats, which was repressed by intra-PVN infusion of the mast cell stabilizer disodium cromoglycate (cromolyn). Wild-type (WT) mice but not mast cell-deficient KitW-sh/W-sh mice that had experienced neonatal MS exhibited chronic visceral hypersensitivity. MS was associated with an increase in the expression of proinflammatory mediators, the number of CRF+ cells and CRF protein in the PVN, which was prevented by intra-PVN infusion of cromolyn. Furthermore, we demonstrated that intra-PVN infusion of the mast degranulator compound 48/80 significantly induced mast cell activation, resulting in proinflammatory mediator release, CRF neuronal sensitization, and visceral hypersensitivity, which was suppressed by cromolyn. Overall, our findings demonstrated that neonatal MS induces the activation of PVN mast cells, which secrete numerous proinflammatory mediators that may participate in neighboring CRF neuronal activity, ultimately directly inducing visceral hypersensitivity in adulthood.
Asunto(s)
Hiperalgesia , Mastocitos , Privación Materna , Núcleo Hipotalámico Paraventricular , Estrés Psicológico , Dolor Visceral , Animales , Masculino , Ratones , Ratas , Animales Recién Nacidos , Modelos Animales de Enfermedad , Hiperalgesia/etiología , Hiperalgesia/inmunología , Hiperalgesia/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones Transgénicos , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas Sprague-Dawley , Dolor Visceral/inmunología , Dolor Visceral/metabolismoRESUMEN
Microbiota has a role in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzes whether MMF improves dysbiosis in a genetic model of hypertension. Twenty weeks old male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were randomly divided into three groups: untreated WKY, untreated SHR, and SHR treated with MMF for 5 weeks. MMF treatment restored gut bacteria from the phyla Firmicutes and Bacteroidetes, and acetate- and lactate-producing bacteria to levels similar to those found in WKY, increasing butyrate-producing bacteria. MMF increased the percentage of anaerobic bacteria in the gut. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. MMF increased the lower regulatory T cells proportion in mesenteric lymph nodes and Th17 and Th1 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that MMF reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity due to reduced sympathetic drive in the gut associated to the reduced brain neuroinflammation.
Asunto(s)
Antihipertensivos/farmacología , Bacterias/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Colon/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Ácido Micofenólico/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/inmunología , Aorta Torácica/fisiopatología , Bacterias/crecimiento & desarrollo , Bacterias/metabolismo , Células Cultivadas , Colon/inervación , Citocinas/metabolismo , Modelos Animales de Enfermedad , Disbiosis , Hipertensión/inmunología , Hipertensión/microbiología , Hipertensión/fisiopatología , Mediadores de Inflamación/metabolismo , Neuroinmunomodulación/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/fisiopatología , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Increased sympathetic nervous system activity is a hallmark of hypertension (HTN), and it is implicated in altered immune system responses in its pathophysiology. However, the precise mechanisms of neural-immune interaction in HTN remain elusive. We have previously shown an association between elevated sympathetic drive to the bone marrow (BM) and activated BM immune cells in rodent models of HTN. Moreover, microglial-dependent neuroinflammation is also seen in rodent models of HTN. However, the cause-effect relationship between central and systemic inflammatory responses and the sympathetic drive remains unknown. These observations led us to hypothesize that increase in the femoral BM sympathetic nerve activity (fSNA) initiates a cascade of events leading to increase in blood pressure (BP). Here, we investigated the temporal relationship between the BM sympathetic drive, activation of the central and peripheral immune system, and increase in BP in the events leading to established HTN. The present study demonstrates that central infusion of angiotensin II (ANG II) induces early microglial activation in the paraventricular nucleus of hypothalamus, which preceded increase in the fSNA. In turn, activation of fSNA correlated with the timing of increased production and release of CD4+.IL17+ T cells and other proinflammatory cells into circulation and elevation in BP, whereas infiltration of CD4+ cells to the paraventricular nucleus marked establishment of ANG II HTN. This study identifies cellular and molecular mechanisms involved in neural-immune interactions in early and established stages of rodent ANG II HTN. NEW & NOTEWORTHY Early microglia activation in paraventricular nucleus precedes sympathetic activation of the bone marrow. This leads to increased bone marrow immune cells and their release into circulation and an increase in blood pressure. Infiltration of CD4+ T cells into paraventricular nucleus paraventricular nucleus marks late hypertension.
Asunto(s)
Presión Sanguínea , Médula Ósea/inervación , Hipertensión/fisiopatología , Inflamación/fisiopatología , Neuroinmunomodulación , Núcleo Hipotalámico Paraventricular/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Angiotensina II , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Modelos Animales de Enfermedad , Fémur , Hipertensión/inducido químicamente , Hipertensión/inmunología , Hipertensión/metabolismo , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Microglía/inmunología , Microglía/metabolismo , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas Sprague-Dawley , Sistema Nervioso Simpático/inmunología , Sistema Nervioso Simpático/metabolismo , Factores de TiempoRESUMEN
The ovarian hormone 17ß-estradiol is known to regulate the release, expression and immunoreactivity of arginine-vasopressin (AVP) in the supraoptic and paraventricular hypothalamic nuclei of rodents. Previous studies have shown that estrogen receptor α is involved in the effects of chronic estradiol administration on arginine-vasopressin immunoreactivity in the female rat hypothalamus. In this study we have examined the effect of an acute administration of estradiol or specific agonists for estrogen receptors α, ß and G protein-coupled estrogen receptor 1 on the immunoreactivity of arginine-vasopressin in the hypothalamus of adult ovariectomized female rats. Acute estradiol administration resulted in a significant decrease in the number of arginine-vasopressin immunoreactive neurons in the supraoptic and paraventricular nuclei after 24â¯h. The effects of the specific estrogen receptors agonists suggest that the action of estradiol on arginine-vasopressin immunoreactivity is mediated in the supraoptic nucleus by G protein-coupled estrogen receptor 1 and in the paraventricular nucleus by both estrogen receptor ß and G protein-coupled estrogen receptor 1. Thus, in contrast to previous studies on the effect of chronic estrogenic treatments, the present findings suggest that estrogen receptor ß and G protein-coupled estrogen receptor 1 mediate the acute effects of estradiol on arginine-vasopressin immunoreactivity in the hypothalamus of ovariectomized rats.
Asunto(s)
Arginina Vasopresina/metabolismo , Receptor beta de Estrógeno/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Núcleo Supraóptico/metabolismo , Animales , Arginina Vasopresina/inmunología , Estradiol/farmacología , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/inmunología , Femenino , Hipotálamo/inmunología , Hipotálamo/metabolismo , Neuronas/inmunología , Neuronas/metabolismo , Ovariectomía , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/inmunología , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/inmunología , Núcleo Supraóptico/efectos de los fármacos , Núcleo Supraóptico/inmunologíaRESUMEN
High dietary salt intake increases risk of stress-related neuropsychiatric disorders. Here, we explored the contribution of high dietary salt intake-induced neuroinflammation in key stress-responsive brain regions, the hypothalamic paraventricular nucleus and basolateral amygdala, in promoting exaggerated neuronal activation and coping behaviors in response to acute psychogenic stress. Mice that underwent high dietary salt intake exhibited increased active stress coping behaviors during and after an acute swim stress, and these were reduced by concurrent administration of minocycline, an inhibitor of microglial activation, without affecting body fluid hyperosmolality caused by high dietary salt intake. Moreover, minocycline attenuated high dietary salt intake-induced increases of paraventricular nucleus tumor necrosis factor-α, activated microglia (ionized calcium-binding adaptor molecule 1), and acute swim stress-induced neuronal activation (c-Fos). In the basolateral amygdala, similar effects were observed on ionized calcium-binding adaptor molecule 1+ and c-Fos+ counts, but not tumor necrosis factor-α levels. These data indicate that high dietary salt intake promotes neuroinflammation, increasing recruitment of neurons in key stress-associated brain regions and augmenting behavioral hyper-responsivity to acute psychological stress.
Asunto(s)
Adaptación Psicológica , Antiinflamatorios/farmacología , Complejo Nuclear Basolateral , Encéfalo , Inflamación , Microglía , Minociclina/farmacología , Núcleo Hipotalámico Paraventricular , Cloruro de Sodio Dietético/efectos adversos , Estrés Psicológico , Adaptación Psicológica/efectos de los fármacos , Animales , Complejo Nuclear Basolateral/efectos de los fármacos , Complejo Nuclear Basolateral/inmunología , Complejo Nuclear Basolateral/metabolismo , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/inmunología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/inmunología , Estrés Psicológico/fisiopatologíaRESUMEN
Systemic inflammation is present in obesity and emerging evidence, primarily from studies using male rodents fed high-fat diets, suggests neuroimmune signaling also is involved. We investigated early changes in neuroimmune signaling during the weight gain that follows ovariectomy in rats. Ovariectomized (OVX) rats were given standard rat chow and terminated 5 days (baseline), 4 or 8 weeks after ovariectomy. Levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in plasma and periuterine adipose were not affected by ovariectomy. In contrast, compared to baseline levels, IL-6 expression in the arcuate nucleus (ARC) and dorsal vagal complex (DVC) decreased by 4 weeks after OVX, but was not affected in the paraventricular nucleus (PVN). MCP-1 expression decreased by 4 weeks in the ARC and by 8 weeks in the PVN, but was not affected in the DVC. Increased glial fibrillary acidic protein (GFAP) expression in the PVN indicated astrocyte activation; decreased toll-like receptor 4 (TLR4) expression in the ARC, but not other regions, suggested early effects on innate immune factors. Importantly, in reproductively intact rats, IL-6 and MCP-1 levels in plasma, periuterine adipose, and brain regions were not affected after 8 weeks. Unlike OVX rats, GFAP expression in the DVC of intact rats was decreased at 8 weeks, and TLR4 expression in the ARC was increased at 8 weeks. Taken together, these dynamic and selective changes in neuroimmune factors co-incident with post-ovariectomy weight gain provide insight into the role of neuroimmune signaling in obesity, particularly in females.
Asunto(s)
Encéfalo/inmunología , Obesidad/etiología , Ovariectomía/efectos adversos , Núcleo Hipotalámico Paraventricular/metabolismo , Aumento de Peso/inmunología , Animales , Encéfalo/metabolismo , Estradiol/metabolismo , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Inflamación/inmunología , Obesidad/inmunología , Núcleo Hipotalámico Paraventricular/inmunología , ARN Mensajero/metabolismo , Ratas Sprague-DawleyRESUMEN
A wide range of stress-related pathologies such as post-traumatic stress disorder are considered to arise from aberrant or maladaptive forms of stress adaptation. The hypothalamic-pituitary-adrenal (HPA) axis readily adapts to repeated stressor exposure, yet little is known about adaptation in neuroimmune responses to repeated or sequential stress challenges. In Experiment 1, rats were exposed to 10 days of restraint alone (60 minutes daily), forced swim alone (30 minutes daily) or daily sequential exposure to restraint (60 minutes) followed immediately by forced swim (30 minutes), termed sequential stress exposure. Habituation of the corticosterone (CORT) response occurred to restraint by 5 days and swim at 10 days, whereas rats exposed to sequential stress exposure failed to display habituation to the combined challenge. Experiment 2 compared 1 or 5 days of forced swim with sequential stress exposure and examined how each affected expression of several neuroimmune and cellular activation genes in the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC) and hippocampus (HPC). Sequential exposure to restraint and swim increased interleukin (IL)-1ß in the PVN, an effect that was attenuated after 5 days. Sequential stress exposure also elicited IL-6 and tumour necrosis factor-α responses in the HPC and PFC, respectively, which did not habituate after 5 days. Experiment 3 tested whether prior habituation to restraint (5 days) would alter the IL-1ß response evoked by swim exposure imposed immediately after the sixth day of restraint. Surprisingly, a history of repeated exposure to restraint attenuated the PVN IL-1ß response after swim in comparison to acutely-exposed subjects despite an equivalent CORT response. Overall, these findings suggest that habituation of neuroimmune responses to stress proceeds: (i) independent of HPA axis habituation; (ii) likely requires more daily sessions of stress to develop; and (iii) IL-1ß displays a greater tendency to habituate after repeated stress challenges compared to other stress-reactive cytokines.
Asunto(s)
Corticosterona/sangre , Habituación Psicofisiológica , Interleucina-1beta/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Estrés Psicológico/metabolismo , Animales , Expresión Génica , Hipocampo/inmunología , Hipocampo/metabolismo , Mediadores de Inflamación , Masculino , Núcleo Hipotalámico Paraventricular/inmunología , Corteza Prefrontal/inmunología , Corteza Prefrontal/metabolismo , Ratas Sprague-Dawley , Restricción Física , Estrés Psicológico/inmunología , NataciónRESUMEN
ANG II is thought to increase sympathetic outflow by increasing oxidative stress and promoting local inflammation in the paraventricular nucleus (PVN) of the hypothalamus. However, the relative contributions of inflammation and oxidative stress to sympathetic drive remain poorly understood, and the underlying cellular and molecular targets have yet to be examined. ANG II has been shown to enhance Toll-like receptor (TLR)4-mediated signaling on microglia. Thus, in the present study, we aimed to determine whether ANG II-mediated activation of microglial TLR4 signaling is a key molecular target initiating local oxidative stress in the PVN. We found TLR4 and ANG II type 1 (AT1) receptor mRNA expression in hypothalamic microglia, providing molecular evidence for the potential interaction between these two receptors. In hypothalamic slices, ANG II induced microglial activation within the PVN (â¼65% increase, P < 0.001), an effect that was blunted in the absence of functional TLR4. ANG II increased ROS production, as indicated by dihydroethidium fluorescence, within the PVN of rats and mice (P < 0.0001 in both cases), effects that were also dependent on the presence of functional TLR4. The microglial inhibitor minocycline attenuated ANG II-mediated ROS production, yet ANG II effects persisted in PVN single-minded 1-AT1a knockout mice, supporting the contribution of a non-neuronal source (likely microglia) to ANG II-driven ROS production in the PVN. Taken together, these results support functional interactions between AT1 receptors and TLR4 in mediating ANG II-dependent microglial activation and oxidative stress within the PVN. More broadly, our results support a functional interaction between the central renin-angiotensin system and innate immunity in the regulation of neurohumoral outflows from the PVN.
Asunto(s)
Angiotensina II/metabolismo , Microglía/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor Toll-Like 4/metabolismo , Angiotensina II/inmunología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Antibacterianos/farmacología , Inmunidad Innata/inmunología , Inflamación , Losartán/farmacología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Noqueados , Microglía/efectos de los fármacos , Microglía/inmunología , Minociclina/farmacología , Estrés Oxidativo/genética , Estrés Oxidativo/inmunología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/inmunología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/inmunología , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/inmunología , Receptor Toll-Like 4/inmunologíaRESUMEN
Exercise training (ExT) is recommended to treat hypertension along with pharmaceutical antihypertensive therapies. Effects of ExT in hypothalamic content of high mobility box 1 (HMGB1) and microglial activation remain unknown. We examined whether ExT would decrease autonomic and cardiovascular abnormalities in spontaneously hypertensive rats (SHR), and whether these effects were associated with decreased HMGB1 content, microglial activation, and inflammation in the hypothalamic paraventricular nucleus (PVN). Normotensive Wistar-Kyoto (WKY) rats and SHR underwent moderate-intensity ExT for 2 wk. After ExT, cardiovascular (heart rate and arterial pressure) and autonomic parameters (arterial pressure and heart rate variability, peripheral sympathetic activity, cardiac vagal activity, and baroreflex function) were measured in conscious and freely-moving rats through chronic arterial and venous catheterization. Cerebrospinal fluid, plasma, and brain were collected for molecular and immunohistochemistry analyses of the PVN. In addition to reduced heart rate variability, decreased vagal cardiac activity and increased mean arterial pressure, heart rate, arterial pressure variability, cardiac, and vasomotor sympathetic activity, SHR had higher HMGB1 protein expression, IκB-α phosphorylation, TNF-α and IL-6 protein expression, and microglia activation in the PVN. These changes were accompanied by higher plasma and cerebrospinal fluid levels of HMGB1. The ExT + SHR group had decreased expression of HMGB1, CXCR4, SDF-1, and phosphorylation of p42/44 and IκB-α. ExT reduced microglial activation and proinflammatory cytokines content in the PVN, and improved autonomic control as well. Data suggest that training-induced downregulation of activated HMGB1/CXCR4/microglia/proinflammatory cytokines axis in the PVN of SHR is a prompt neural adaptation to counterbalance the deleterious effects of inflammation on autonomic control.
Asunto(s)
Citocinas/metabolismo , Proteína HMGB1/metabolismo , Microglía/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Condicionamiento Físico Animal , Sistema Nervioso Simpático/fisiopatología , Animales , Presión Arterial , Sistema Nervioso Autónomo/fisiología , Sistema Nervioso Autónomo/fisiopatología , Barorreflejo/fisiología , Citocinas/inmunología , Frecuencia Cardíaca/fisiología , Proteínas I-kappa B/metabolismo , Inflamación , Interleucina-6/inmunología , Interleucina-6/metabolismo , Microglía/fisiología , Inhibidor NF-kappaB alfa , Núcleo Hipotalámico Paraventricular/inmunología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores CXCR4/inmunología , Receptores CXCR4/metabolismo , Transducción de Señal , Sistema Nervioso Simpático/fisiología , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Nervio Vago/fisiología , Nervio Vago/fisiopatologíaRESUMEN
Epidemiological evidence suggests that the consumption of a diet high in n-6 polyunsaturated fatty acids (PUFA) is associated with the development of leptin resistance and obesity. We aim to examine the central effect of n-6 PUFA, arachidonic acid (ARA) on leptin sensitivity and leptin-regulated hepatic glucose and lipid metabolism. We found that intracerebroventricular injection of ARA (25 nmol/day) for 2.5 days reversed the effect of central leptin on hypothalamic JAK2, pSTAT3, pAkt, and pFOXO1 protein levels, which was concomitant with a pro-inflammatory response in the hypothalamus. ARA also attenuated the effect of central leptin on hepatic glucose and lipid metabolism by reversing the mRNA expression of the genes involved in gluconeogenesis (G6Pase, PEPCK), glucose transportation (GLUT2), lipogenesis (FAS, SCD1), and cholesterol synthesis (HMG-CoA reductase). These results indicate that an increased exposure to central n-6 PUFA induces central cellular leptin resistance with concomitant defective JAK2-STAT3 and PI3K-Akt signaling.
Asunto(s)
Ácido Araquidónico/farmacología , Metabolismo Energético , Leptina/fisiología , Hígado/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Animales , Ingestión de Energía , Glucosa/metabolismo , Homeostasis , Hipotálamo/inmunología , Hipotálamo/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones Endogámicos C57BL , Núcleo Hipotalámico Paraventricular/inmunología , Transducción de Señal , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The 'sick euthyroid syndrome' or 'non-thyroidal illness syndrome' (NTIS) occurs in a large proportion of hospitalized patients and comprises a variety of alterations in the hypothalamus-pituitary-thyroid (HPT) axis that are observed during illness. One of the hallmarks of NTIS is decreased thyroid hormone (TH) serum concentrations, often viewed as an adaptive mechanism to save energy. Downregulation of hypophysiotropic TRH neurons in the paraventricular nucleus of the hypothalamus and of TSH production in the pituitary gland points to disturbed negative feedback regulation during illness. In addition to these alterations in the central component of the HPT axis, changes in TH metabolism occur in a variety of TH target tissues during NTIS, dependent on the timing, nature and severity of the illness. Cytokines, released during illness, are known to affect a variety of genes involved in TH metabolism and are therefore considered a major determinant of NTIS. The availability of in vivo and in vitro models for NTIS has elucidated part of the mechanisms involved in the sometimes paradoxical changes in the HPT axis and TH responsive tissues. However, the pathogenesis of NTIS is still incompletely understood. This review focusses on the molecular mechanisms involved in the tissue changes in TH metabolism and discusses the gaps that still require further research.
Asunto(s)
Síndromes del Eutiroideo Enfermo/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Modelos Biológicos , Sistema Hipófiso-Suprarrenal/metabolismo , Animales , Síndromes del Eutiroideo Enfermo/inmunología , Síndromes del Eutiroideo Enfermo/fisiopatología , Regulación de la Expresión Génica , Humanos , Sistema Hipotálamo-Hipofisario/inmunología , Sistema Hipotálamo-Hipofisario/fisiopatología , Mediadores de Inflamación/metabolismo , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/enzimología , Neuronas/inmunología , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/fisiopatología , Sistema Hipófiso-Suprarrenal/inmunología , Sistema Hipófiso-Suprarrenal/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
RATIONALE: Microglial activation in autonomic brain regions is a hallmark of neuroinflammation in neurogenic hypertension. Despite evidence that an impaired sympathetic nerve activity supplying the bone marrow (BM) increases inflammatory cells and decreases angiogenic cells, little is known about the reciprocal impact of BM-derived inflammatory cells on neuroinflammation in hypertension. OBJECTIVE: To test the hypothesis that proinflammatory BM cells from hypertensive animals contribute to neuroinflammation and hypertension via a brain-BM interaction. METHODS AND RESULTS: After BM ablation in spontaneously hypertensive rats, and reconstitution with normotensive Wistar Kyoto rat BM, the resultant chimeric spontaneously hypertensive rats displayed significant reduction in mean arterial pressure associated with attenuation of both central and peripheral inflammation. In contrast, an elevated mean arterial pressure along with increased central and peripheral inflammation was observed in chimeric Wistar-Kyoto rats reconstituted with spontaneously hypertensive rat BM. Oral treatment with minocycline, an inhibitor of microglial activation, attenuated hypertension in both the spontaneously hypertensive rats and the chronic angiotensin II-infused rats. This was accompanied by decreased sympathetic drive and inflammation. Furthermore, in chronic angiotensin II-infused rats, minocycline prevented extravasation of BM-derived cells to the hypothalamic paraventricular nucleus, presumably via a mechanism of decreased C-C chemokine ligand 2 levels in the cerebrospinal fluid. CONCLUSIONS: The BM contributes to hypertension by increasing peripheral inflammatory cells and their extravasation into the brain. Minocycline is an effective therapy to modify neurogenic components of hypertension. These observations support the hypothesis that BM-derived cells are involved in neuroinflammation, and targeting them may be an innovative strategy for neurogenic resistant hypertension therapy.
Asunto(s)
Células de la Médula Ósea/fisiología , Hipertensión/etiología , Microglía/fisiología , Inflamación Neurogénica/complicaciones , Núcleo Hipotalámico Paraventricular/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Angiotensina II , Animales , Barorreflejo/fisiología , Trasplante de Médula Ósea , Quimiocina CCL2/biosíntesis , Quimiocina CCL2/genética , Femenino , Hipertensión/fisiopatología , Hipertensión/prevención & control , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Masculino , Microglía/efectos de los fármacos , Minociclina/uso terapéutico , Norepinefrina/sangre , Núcleo Hipotalámico Paraventricular/inmunología , Quimera por Radiación , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Sistema Nervioso Simpático/efectos de los fármacos , Subgrupos de Linfocitos T/inmunologíaRESUMEN
We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar-Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocyte diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (ß-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy.
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Cardiomegalia/prevención & control , Citocinas/metabolismo , Hipertensión/tratamiento farmacológico , Mediadores de Inflamación/metabolismo , Estrés Oxidativo/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Pirrolidinas/farmacología , Tiocarbamatos/farmacología , Factor de Transcripción ReIA/antagonistas & inhibidores , Animales , Presión Arterial/efectos de los fármacos , Biomarcadores/metabolismo , Cardiomegalia/etiología , Cardiomegalia/inmunología , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Modelos Animales de Enfermedad , Hipertensión/complicaciones , Hipertensión/inmunología , Hipertensión/metabolismo , Hipertensión/fisiopatología , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transducción de Señal/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/fisiopatología , Factores de Tiempo , Factor de Transcripción ReIA/metabolismoRESUMEN
Sickness behavior is a series of behavioral and psychological changes that develop in inflammatory disease, including infections and cancers. Administration of the bacterial endotoxin lipopolysaccharide (LPS) induces sickness behavior in rodents. Genipin, an aglycon derived from an iridoid glycoside geniposide extracted from the fruit of Gardenia jasminoides, has anti-inflammatory and antidepressant activities. However, the effects of genipin on inflammation-induced changes in emotional behaviors are unknown. In this study, we examined the effects of genipin on LPS-induced inflammation in BV-2 cells and sickness behavior in mice. Pretreatment with genipin inhibited LPS-induced increases in NO production and reduced the mRNA levels of inflammation-related genes (iNOS, COX-2, IL-1ß and IL-6) in BV-2 cells. Oral administration of genipin ameliorated LPS-induced depressive-like behavior in the forced swim test and social behavior deficits 24h after LPS administration in mice. LPS-induced expression of mRNAs for inflammation-related genes and the number of c-fos immunopositive cells decreased in the paraventricular nucleus (PVN) of the hypothalamus and the central nucleus of the amygdala (CeA), suggesting that genipin attenuates LPS-induced changes of emotional behaviors through inhibition of neural activation and inflammatory responses in the PVN and CeA. These novel pharmacological effects of genipin may be useful for treatment of patients with sickness behavior.
Asunto(s)
Núcleo Amigdalino Central/efectos de los fármacos , Emociones/efectos de los fármacos , Conducta de Enfermedad/efectos de los fármacos , Iridoides/farmacología , Lipopolisacáridos/toxicidad , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Núcleo Amigdalino Central/inmunología , Núcleo Amigdalino Central/metabolismo , Emociones/fisiología , Conducta de Enfermedad/fisiología , Lipopolisacáridos/antagonistas & inhibidores , Masculino , Ratones , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/metabolismo , RubiaceaeRESUMEN
The early life period is one of significant vulnerability to programming effects from the environment. Given the sensitivity of microglial cells to early life programming and to adult diet, we hypothesized overfeeding during the neonatal period would acutely alter microglial profiles within the developing brain, predisposing the individual to a lasting central pro-inflammatory profile that contributes to overactive immune responses long-term. We tested this idea by manipulating litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of 4 (neonatally overfed) or 12 (control). This manipulation induces obesity and susceptibility to lipopolysaccharide (LPS) long-term. We then examined microglial and central pro-inflammatory profiles during development and in adulthood as well as susceptibility to neuroimmune challenge with LPS. Neonatally overfed rats have evidence of microgliosis in the paraventricular nucleus of the hypothalamus (PVN) as early as postnatal day 14. They also show changes in hypothalamic gene expression at this time, with suppressed hypothalamic interleukin 1ß mRNA. These effects persist into adulthood, with basal PVN microgliosis and increased hypothalamic toll-like receptor 4, nuclear factor κB, and interleukin 6 gene expression. These neonatally overfed rats also have dramatically exacerbated microglial activation in the PVN 24h after an adult LPS challenge, coupled with changes in inflammatory gene expression. Thus, it appears neonatal overfeeding sensitizes PVN microglia, contributing to a basal pro-inflammatory profile and an altered response to a neuroimmune challenge throughout life. It remains to be seen if these effects can be reversed with early interventions.
Asunto(s)
Trastornos de la Nutrición del Lactante/inmunología , Sobrepeso/inmunología , Núcleo Hipotalámico Paraventricular/inmunología , Animales , Animales Recién Nacidos , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Femenino , Regulación del Desarrollo de la Expresión Génica , Humanos , Trastornos de la Nutrición del Lactante/genética , Trastornos de la Nutrición del Lactante/patología , Recién Nacido , Inflamación/etiología , Inflamación/genética , Inflamación/inmunología , Lipopolisacáridos/toxicidad , Tamaño de la Camada , Masculino , FN-kappa B/biosíntesis , FN-kappa B/genética , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Neuroinmunomodulación/fisiología , Sobrepeso/etiología , Sobrepeso/genética , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/patología , Embarazo , Ratas , Ratas Wistar , Método Simple Ciego , Receptor Toll-Like 4/biosíntesis , Receptor Toll-Like 4/genética , Aumento de PesoRESUMEN
The hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) play a critical role in the generation and maintenance of sympathetic nerve activity. The renin-angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. This study was designed to determine whether inhibition of the angiotensin-converting enzyme (ACE) in the PVN modulates cytokines and attenuates oxidative stress (ROS) in the RVLM, and decreases the blood pressure and sympathetic activity in renovascular hypertensive rats. Renovascular hypertension was induced in male Sprague-Dawley rats by the two-kidney one-clip (2K1C) method. Renovascular hypertensive rats received bilateral PVN infusion with ACE inhibitor lisinopril (LSP, 10µg/h) or vehicle via osmotic minipump for 4weeks. Mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma proinflammatory cytokines (PICs) were significantly increased in renovascular hypertensive rats. The renovascular hypertensive rats also had higher levels of ACE in the PVN, and lower level of interleukin-10 (IL-10) in the RVLM. In addition, the levels of PICs, the chemokine MCP-1, the subunit of NAD(P)H oxidase (gp91(phox)) and ROS in the RVLM were increased in hypertensive rats. PVN treatment with LSP attenuated those changes occurring in renovascular hypertensive rats. Our findings suggest that the beneficial effects of ACE inhibition in the PVN in renovascular hypertension are partly due to modulation cytokines and attenuation oxidative stress in the RVLM.
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Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Antihipertensivos/administración & dosificación , Citocinas/metabolismo , Hipertensión Renovascular/tratamiento farmacológico , Mediadores de Inflamación/metabolismo , Lisinopril/administración & dosificación , Bulbo Raquídeo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Animales , Antiinflamatorios/administración & dosificación , Antioxidantes/administración & dosificación , Presión Arterial/efectos de los fármacos , Quimiocina CCL2/metabolismo , Citocinas/sangre , Modelos Animales de Enfermedad , Hipertensión Renovascular/inmunología , Hipertensión Renovascular/metabolismo , Hipertensión Renovascular/fisiopatología , Mediadores de Inflamación/sangre , Infusiones Parenterales , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Masculino , Bulbo Raquídeo/inmunología , Bulbo Raquídeo/metabolismo , Bulbo Raquídeo/fisiopatología , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasa 2 , NADPH Oxidasas/metabolismo , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/fisiopatología , Peptidil-Dipeptidasa A/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Factores de TiempoRESUMEN
BACKGROUND: Microglia of the central nervous system act as sentinels and rapidly react to infection or inflammation. The pathophysiological role of bone marrow-derived microglia is of particular interest because they affect neurodegenerative disorders and neuropathic pain. The hypothesis of the current study is that chronic psychological stress (chronic PS) induces the infiltration of bone marrow-derived microglia into hypothalamus by means of chemokine axes in brain and bone marrow. METHODS AND FINDINGS: Here we show that bone marrow-derived microglia specifically infiltrate the paraventricular nucleus (PVN) of mice that received chronic PS. Bone marrow derived-microglia are CX3CR1(low)CCR2(+)CXCR4(high), as distinct from CX3CR1(high)CCR2(-)CXCR4(low) resident microglia, and express higher levels of interleukin-1ß (IL-1ß) but lower levels of tumor necrosis factor-α (TNF-α). Chronic PS stimulates the expression of monocyte chemotactic protein-1 (MCP-1) in PVN neurons, reduces stromal cell-derived factor-1 (SDF-1) in the bone marrow and increases the frequency of CXCR4(+) monocytes in peripheral circulation. And then a chemokine (C-C motif) receptor 2 (CCR2) or a ß3-adrenoceptor blockade prevents infiltration of bone marrow-derived microglia in the PVN. CONCLUSION: Chronic PS induces the infiltration of bone marrow-derived microglia into PVN, and it is conceivable that the MCP-1/CCR2 axis in PVN and the SDF-1/CXCR4 axis in bone marrow are involved in this mechanism.
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Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Microglía/inmunología , Microglía/patología , Núcleo Hipotalámico Paraventricular/patología , Estrés Psicológico/inmunología , Estrés Psicológico/patología , Animales , Células de la Médula Ósea/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CXCL12/metabolismo , Quimiotaxis/inmunología , Hipotálamo/inmunología , Hipotálamo/metabolismo , Hipotálamo/patología , Interleucina-1beta/metabolismo , Masculino , Ratones , Microglía/metabolismo , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/metabolismo , ARN Mensajero/genética , Receptores CCR2/metabolismo , Receptores CXCR4/metabolismo , Receptores de Interleucina-1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Estrés Psicológico/genética , Estrés Psicológico/metabolismoRESUMEN
Systemic inflammatory response syndrome is associated with either fever or hypothermia, but the mechanisms responsible for switching from one to the other are unknown. In experimental animals, systemic inflammation is often induced by bacterial lipopolysaccharide (LPS). To identify the diencephalic and brainstem structures involved in the fever-hypothermia switch, we studied the expression of c-Fos protein, a marker of neuronal activation, in rats treated with the same high dose of LPS (0.5 mg/kg, intravenously) either in a thermoneutral (30 °C) or cool (24 °C) environment. At 30 °C, LPS caused fever; at 24 °C, the same dose caused profound hypothermia. Both fever and hypothermia were associated with the induction of c-Fos in many brain areas, including several structures of the anterior preoptic, paraventricular, lateral, and dorsal hypothalamus, the bed nucleus of the stria terminalis, the posterior pretectal nucleus, ventrolateral periaqueductal gray, lateral parabrachial nucleus, area postrema, and nucleus of the solitary tract. Every brain area studied showed a comparable response to LPS at the two different ambient temperatures used, with the exception of two areas: the dorsomedial hypothalamic nucleus (DMH), which we studied together with the adjacent dorsal hypothalamic area (DA), and the paraventricular hypothalamic nucleus (PVH). Both structures had much stronger c-Fos expression during LPS hypothermia than during fever. We propose that PVH and DMH/DA neurons are involved in a circuit, which - depending on the ambient temperature - determines whether the thermoregulatory response to bacterial LPS will be fever or hypothermia.
Asunto(s)
Núcleo Hipotalámico Dorsomedial/metabolismo , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Animales , Regulación de la Temperatura Corporal , Núcleo Hipotalámico Dorsomedial/inmunología , Expresión Génica , Lipopolisacáridos/inmunología , Masculino , Neuronas/inmunología , Núcleo Hipotalámico Paraventricular/inmunología , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , TemperaturaRESUMEN
Rising rates of maternal obesity/overweight bring the need for effective interventions in offspring. We observed beneficial effects of postweaning exercise, but the question of whether late-onset exercise might benefit offspring exposed to maternal obesity is unanswered. Thus we examined effects of voluntary exercise implemented in adulthood on adiposity, hormone profiles, and genes involved in regulating appetite and metabolism in female offspring. Female Sprague Dawley rats were fed either normal chow or high-fat diet (HFD) ad libitum for 5 weeks before mating and throughout gestation/lactation. At weaning, female littermates received either chow or HFD and, after 7 weeks, half were exercised (running wheels) for 5 weeks. Tissues were collected at 15 weeks. Maternal obesity was associated with increased hypothalamic inflammatory markers, including suppressor of cytokine signaling 3, TNF-α, IL-1ß, and IL-6 expression in the arcuate nucleus. In the paraventricular nucleus (PVN), Y1 receptor, melanocortin 4 receptor, and TNF-α mRNA were elevated. In the hippocampus, maternal obesity was associated with up-regulated fat mass and obesity-associated gene and TNF-α mRNA. We observed significant hypophagia across all exercise groups. In female offspring of lean dams, the reduction in food intake by exercise could be related to altered signaling at the PVN melanocortin 4 receptor whereas in offspring of obese dams, this may be related to up-regulated TNF-α. Late-onset exercise ameliorated the effects of maternal obesity and postweaning HFD in reducing body weight, adiposity, plasma leptin, insulin, triglycerides, and glucose intolerance, with greater beneficial effects in offspring of obese dams. Overall, hypothalamic inflammation was increased by maternal obesity or current HFD, and the effect of exercise was dependent on maternal diet. In conclusion, even after a significant sedentary period, many of the negative impacts of maternal obesity could be improved by voluntary exercise and healthy diet.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Lactancia , Fenómenos Fisiologicos Nutricionales Maternos , Actividad Motora , Obesidad/fisiopatología , Sobrepeso/prevención & control , Complicaciones del Embarazo/fisiopatología , Adiposidad , Animales , Regulación del Apetito , Conducta Animal , Femenino , Desarrollo Fetal , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Leptina/sangre , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/inmunología , Neuronas/metabolismo , Sobrepeso/etiología , Sobrepeso/inmunología , Sobrepeso/metabolismo , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Regulación hacia ArribaRESUMEN
The experiments show that hypoxia training leads to an increase of the immunoreactivity to corticotropin and beta-endorphin and to an increase of the content of these neuropeptides. In this case, the ratio of the area of the immunoreactive material to the corticotropin/beta-endorphin, and the coefficient of their content in the PVN did not change significantly compared with the control. Thus, the selected hypoxia mode leads to adaptation, which is reflected in the balanced activity of stress-realizing and stress-limiting systems of rats' hypothalamus.