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1.
Proc Natl Acad Sci U S A ; 114(30): E6107-E6116, 2017 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-28696309

RESUMEN

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally, Cxcl5 expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases.


Asunto(s)
Encefalomielitis Autoinmune Experimental/complicaciones , Infecciones por Orthomyxoviridae/complicaciones , Animales , Cerebelo/inmunología , Cerebelo/metabolismo , Quimiocina CXCL5/inmunología , Quimiocina CXCL5/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Vigilancia Inmunológica , Alphainfluenzavirus , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Médula Espinal/inmunología , Médula Espinal/metabolismo , Transcriptoma
2.
Brain Behav Immun ; 80: 763-776, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31108171

RESUMEN

Acute stressors can induce fear and physiologic responses that prepare the body to protect from danger. A key component of this response is immune system readiness. In particular, inflammasome activation appears critical to linking stress to the immune system. Here, we show that a novel combination of handling procedures used regularly in mouse research impairs novel object recognition (NOR) and activates caspase-1 in the amygdala. In male mice, this handling-stress paradigm combined weighing, scruffing and sham abdominal injection once per hr. While one round of weigh/scruff/needle-stick had no impact on NOR, two rounds compromised NOR without impacting location memory or anxiety-like behaviors. Caspase-1 knockout (KO), IL-1 receptor 1 (IL-1R1) KO and IL-1 receptor antagonist (IL-RA)-administered mice were resistant to handling stress-induced loss of NOR. In addition, examination of the brain showed that handling stress increased caspase-1 activity 85% in the amygdala without impacting hippocampal caspase-1 activity. To delineate danger signals relevant to handling stress, caffeine-administered and adenosine 2A receptor (A2AR) KO mice were tested and found resistant to impaired learning and caspase-1 activation. Finally, mice treated with the ß-adrenergic receptor antagonist, propranolol, were resistant to handling stress-induced loss of NOR and caspase-1 activation. Taken together, these results indicate that handling stress-induced impairment of object learning is reliant on a pathway requiring A2AR-dependent activation of caspase-1 in the amygdala that appears contingent on ß-adrenergic receptor functionality.


Asunto(s)
Adenosina/metabolismo , Caspasa 1/metabolismo , Aprendizaje/fisiología , Estrés Psicológico/metabolismo , Adenosina/farmacología , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad , Encéfalo/metabolismo , Activación Enzimática , Miedo/fisiología , Hipocampo/metabolismo , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Receptores Purinérgicos P1/metabolismo , Transducción de Señal/efectos de los fármacos
3.
Epilepsia ; 60(4): 626-635, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30770561

RESUMEN

OBJECTIVE: Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3-dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N-methyl-d-aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis. METHODS: C57BL/6J and Ido1 knockout mice (Ido1-KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real-time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry. RESULTS: Infected C57BL/6J mice up-regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1-KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1-KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1-KO mice. SIGNIFICANCE: Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.


Asunto(s)
Encefalitis Viral/complicaciones , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Convulsiones/enzimología , Animales , Infecciones por Cardiovirus/complicaciones , Modelos Animales de Enfermedad , Encefalitis Viral/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Convulsiones/virología , Theilovirus
4.
Behav Genet ; 45(4): 451-60, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25772794

RESUMEN

Inflammation is a recognized antecedent and coincident factor when examining the biology of anxiety. Little is known, however, about how reductions in endogenous anti-inflammatory mediators impact anxiety. Therefore, mood- cognition- and anxiety-associated/like behaviors were examined in IL-4 knock out (KO) mice and wild-type (WT) mice. In comparison to WT mice, IL-4 KO mice demonstrated decreased burrowing and increased social exploration. No differences were seen in forced swim or saccharine preference testing. IL-4 KO mice had similar performance to WT mice in the Morris water maze and during object location and novel object recognition. In the elevated zero-maze, IL-4 KO mice, in comparison to WT mice, demonstrated anxiety-like behavior. Anxiety-like behavior in IL-4 KO mice was not observed, however, during open-field testing. Taken together, these data indicate that IL-4 KO mice display state, but not trait, anxiety suggesting that reductions in endogenous anti-inflammatory bioactives can engender subtypes of anxiety.


Asunto(s)
Ansiedad/genética , Conducta Animal , Inflamación , Interleucina-4/genética , Animales , Conducta Exploratoria , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Conducta Social , Natación
5.
Brain Behav Immun ; 41: 218-31, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24907587

RESUMEN

Anxiety is one of the most commonly reported psychiatric conditions, but its pathogenesis is poorly understood. Ailments associated with activation of the innate immune system, however, are increasingly linked to anxiety disorders. In adult male mice, we found that adenosine doubled caspase-1 activity in brain by a pathway reliant on ATP-sensitive potassium (KATP) channels, protein kinase A (PKA) and the A2A adenosine receptor (AR). In addition, adenosine-dependent activation of caspase-1 increased interleukin (IL)-1ß in the brain by 2-fold. Peripheral administration of adenosine in wild-type (WT) mice led to a 2.3-fold increase in caspase-1 activity in the amygdala and to a 33% and 42% reduction in spontaneous locomotor activity and food intake, respectively, that were not observed in caspase-1 knockout (KO), IL-1 receptor type 1 (IL-1R1) KO and A2A AR KO mice or in mice administered a caspase-1 inhibitor centrally. Finally, adenosine administration increased anxiety-like behaviors in WT mice by 28% in the open field test and by 55% in the elevated zero-maze. Caspase-1 KO mice, IL-1R1 KO mice, A2A AR KO mice and WT mice treated with the KATP channel blocker, glyburide, were resistant to adenosine-induced anxiety-like behaviors. Thus, our results indicate that adenosine can act as an anxiogenic by activating caspase-1 and increasing IL-1ß in the brain.


Asunto(s)
Adenosina/toxicidad , Ansiedad/inducido químicamente , Encéfalo/metabolismo , Caspasa 1/fisiología , Interleucina-1beta/biosíntesis , Proteínas del Tejido Nervioso/fisiología , Receptor de Adenosina A2A/fisiología , Adenosina/farmacología , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/fisiopatología , Carbazoles/farmacología , Caspasa 1/deficiencia , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Activación Enzimática/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Gliburida/farmacología , Interleucina-1beta/genética , Interleucina-1beta/fisiología , Transporte Iónico/efectos de los fármacos , Canales KATP/fisiología , Locomoción/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/deficiencia , Potasio/metabolismo , Pirroles/farmacología , Receptor de Adenosina A2A/deficiencia , Receptor de Adenosina A2A/efectos de los fármacos , Receptores Tipo I de Interleucina-1/deficiencia , Receptores Tipo I de Interleucina-1/fisiología
6.
J Neurosci ; 32(40): 13945-55, 2012 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-23035103

RESUMEN

After hypoxia, a critical adverse outcome is the inability to create new memories. How anterograde amnesia develops or resolves remains elusive, but a link to brain-based IL-1 is suggested due to the vital role of IL-1 in both learning and brain injury. We examined memory formation in mice exposed to acute hypoxia. After reoxygenation, memory recall recovered faster than memory formation, impacting novel object recognition and cued fear conditioning but not spatially cued Y-maze performance. The ability of mice to form new memories after hypoxia/reoxygenation was accelerated in IL-1 receptor 1 knockout (IL-1R1 KO) mice, in mice receiving IL-1 receptor antagonist (IL-1RA), and in mice given the caspase 1 inhibitor Ac-YVAD-CMK. Mechanistically, hypoxia/reoxygenation more than doubled caspase 1 activity in the brain, which was localized to the amygdala compared to the hippocampus. This reoxygenation-dependent activation of caspase 1 was prevented by broad-spectrum adenosine receptor (AR) antagonism with caffeine and by targeted A1/A2A AR antagonism with 8-cyclopentyl-1,3-dipropylxanthine plus 3,7-dimethyl-1-propargylxanthine. Additionally, perfusion of adenosine activated caspase 1 in the brain, while caffeine blocked this action by adenosine. Finally, resolution of anterograde amnesia was improved by both caffeine and by targeted A1/A2A AR antagonism. These findings indicate that amygdala-based anterograde amnesia after hypoxia/reoxygenation is sustained by IL-1ß generated through adenosine-dependent activation of caspase 1 after reoxygenation.


Asunto(s)
Adenosina/fisiología , Amnesia Anterógrada/enzimología , Amígdala del Cerebelo/fisiología , Caspasa 1/fisiología , Hipoxia Encefálica/complicaciones , Adenosina/farmacología , Clorometilcetonas de Aminoácidos/farmacología , Amnesia Anterógrada/etiología , Amnesia Anterógrada/fisiopatología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/enzimología , Animales , Cafeína/farmacología , Caspasa 1/efectos de los fármacos , Inhibidores de Caspasas/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Señales (Psicología) , Activación Enzimática , Miedo/efectos de los fármacos , Miedo/fisiología , Hipoxia Encefálica/fisiopatología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Sistema de Señalización de MAP Quinasas , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Recuerdo Mental , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oxígeno/metabolismo , Oxígeno/farmacología , Receptores Tipo I de Interleucina-1/deficiencia , Receptores Purinérgicos P1/fisiología , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Teobromina/análogos & derivados , Teobromina/farmacología , Xantinas/farmacología
7.
Nat Rev Neurosci ; 9(1): 46-56, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18073775

RESUMEN

In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.


Asunto(s)
Encéfalo/fisiopatología , Depresión/etiología , Enfermedad/etiología , Sistema Inmunológico/fisiopatología , Inflamación/complicaciones , Inflamación/fisiopatología , Animales , Citocinas/metabolismo , Depresión/metabolismo , Enfermedad/psicología , Humanos , Inflamación/inmunología , Inflamación/metabolismo
8.
Brain Behav Immun ; 32: 1-8, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23195532

RESUMEN

The cytokine IL-1 is critical to the pathogenesis of a variety of human conditions and diseases. Unlike most other cytokines, IL-1 is counterbalanced by two endogenous inhibitors. The functional significance of IL-1 receptor antagonist (IL-1RA) is well documented due to the clinical utilization of the recombinant human IL-1RA analog, anakinra. In contrast, much less is known about the type 2 IL-1 receptor (IL-1R2), which acts as a decoy receptor for IL-1. While IL-1R2 is structurally similar to the type 1 IL-1 receptor (IL-1R1) responsible for IL-1 signal transduction, its truncated cytoplasmic domain and lack of Toll-IL-1 receptor (TIR) region renders IL-1R2 incapable of transmembrane signaling. IL-1R2 competes with IL-1R1 for ligands and for the IL-1R1 co-receptor, IL-1 receptor accessory protein (IL-1RAP). Additionally, IL-1R2 exists in both a membrane bound and soluble form (sIL-1R2) that has biological properties similar to both a decoy receptor and a binding protein. Thus far, IL-1R2 has been implicated in arthritis, endometriosis, organ transplantation, sepsis/sickness behavior, diabetes, atherosclerosis, autoimmune inner ear disease (AIED), Alzheimer's disease and ulcerative colitis. In this review, we will detail the functional properties of IL-1R2 and examine its role in human disease.


Asunto(s)
Sistema Inmunológico/fisiología , Receptores Tipo II de Interleucina-1/fisiología , Animales , Enfermedades Autoinmunes/inmunología , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Trasplante de Órganos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores Tipo II de Interleucina-1/genética
9.
Brain Behav Immun ; 30: 66-72, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23354002

RESUMEN

During systemic infection, inflammatory cytokines such as interleukin (IL)-6 are produced in excess in the brain of aged mice and induce severe behavioral deficits. However, no studies have examined how pro-inflammatory IL-6 trans-signaling is involved in the exaggerated production of IL-6 in the aged brain, nor the extent to which IL-6 trans-signaling affects other markers of neuroinflammation, adhesion molecules, and behavior. Therefore, this study investigated in aged mice the presence of IL-6 signaling subunits in microglia; the central effects of soluble gp130 (sgp130)-a natural inhibitor of the IL-6 trans-signaling pathway-on IL-6 production in microglia; and the effects of sgp130 given intracerebroventricularly (ICV) on neuroinflammation and sickness behavior caused by i.p. injection of lipopolysaccharide (LPS). Here we show that microglia isolated from aged mice have higher expression of IL-6 receptor (IL-6R) compared to microglia from adults; and the level of mRNA for ADAM17, the enzyme responsible for shedding membrane-bound IL-6R in trans-signaling, is higher in the hippocampus of aged mice compared to adults. Additionally, we show in aged mice that peripheral LPS challenge elicits a hyperactive IL-6 response in microglia, and selective blockade of trans-signaling by ICV injection of sgp130 mitigates this. The sgp130-associated inhibition of IL-6 was paralleled by amelioration of exaggerated and protracted sickness behavior in aged mice. Taken together, the results show that microglia are important regulators of the IL-6 trans-signaling response in the aged brain and sgp130 exerts an anti-inflammatory effect by inhibiting the pro-inflammatory arm of IL-6 signaling.


Asunto(s)
Antiinflamatorios/farmacología , Encéfalo/efectos de los fármacos , Receptor gp130 de Citocinas/farmacología , Encefalitis/inmunología , Conducta de Enfermedad/efectos de los fármacos , Interleucina-6/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/inmunología , Encéfalo/metabolismo , Encefalitis/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Hipocampo/metabolismo , Conducta de Enfermedad/fisiología , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratones , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/metabolismo , Transducción de Señal/inmunología
10.
Brain Behav Immun ; 26(2): 218-27, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21958477

RESUMEN

In the clinical setting, repeated exposures (10-30) to low-doses of ionizing radiation (≤200 cGy), as seen in radiotherapy for cancer, causes fatigue. Almost nothing is known, however, about the fatigue inducing effects of a single exposure to environmental low-dose ionizing radiation that might occur during high-altitude commercial air flight, a nuclear reactor accident or a solar particle event (SPE). To investigate the short-term impact of low-dose ionizing radiation on mouse biobehaviors and neuroimmunity, male CD-1 mice were whole body irradiated with 50 cGy or 200 cGy of gamma or proton radiation. Gamma radiation was found to reduce spontaneous locomotor activity by 35% and 36%, respectively, 6 h post irradiation. In contrast, the motivated behavior of social exploration was un-impacted by gamma radiation. Examination of pro-inflammatory cytokine gene transcripts in the brain demonstrated that gamma radiation increased hippocampal TNF-α expression as early as 4 h post-irradiation. This was coupled to subsequent increases in IL-1RA (8 and 12 h post irradiation) in the cortex and hippocampus and reductions in activity-regulated cytoskeleton-associated protein (Arc) (24 h post irradiation) in the cortex. Finally, restraint stress was a significant modulator of the neuroimmune response to radiation blocking the ability of 200 cGy gamma radiation from impairing locomotor activity and altering the brain-based inflammatory response to irradiation. Taken together, these findings indicate that low-dose ionizing radiation rapidly activates the neuroimmune system potentially causing early onset fatigue-like symptoms in mice.


Asunto(s)
Neuroinmunomodulación/efectos de la radiación , Radiación Ionizante , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/efectos de la radiación , Proteínas del Citoesqueleto , Relación Dosis-Respuesta en la Radiación , Conducta Exploratoria/efectos de la radiación , Fatiga/inducido químicamente , Rayos gamma , Hipocampo/metabolismo , Hipocampo/efectos de la radiación , Proteína Antagonista del Receptor de Interleucina 1/biosíntesis , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Proteínas del Tejido Nervioso , Restricción Física/psicología , Factores de Tiempo , Factor de Necrosis Tumoral alfa/biosíntesis , Irradiación Corporal Total
11.
Brain Behav Immun ; 26(6): 951-8, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22561683

RESUMEN

Use of individually ventilated caging (IVC) systems for mouse-based laboratory investigation has dramatically increased. We found that without mice present, intra-cage oxygen concentration was comparable (21%) between IVC housing and ambient environment caging (AEC) that used wire top lids. However, when mice were housed 4-to-a-cage for 1week, intra-cage oxygen dropped to 20.5% in IVC housing as compared to 21% for AEC housing. IVC intra-cage humidity was also elevated relative to AEC housing. Mice raised in IVC housing as compared to mice raised in AEC housing had higher RBC mass, hematocrit and hemoglobin concentrations. They also had elevated platelet counts but lower white blood cell counts. IVC mice, relative to AEC mice, had increased saccharin preference and increased fluid consumption but similar locomotion, food intake, social exploration and novel object recognition when tested in an AEC environment. Taken together, these data indicate that ventilated caging systems can have a 0.5% reduction from ambient oxygen concentration that is coupled to mouse red blood cell indices indicative of chronic exposure to a hypoxia. Importantly, IVC housing can impact behavioral testing for depressive-like behavior.


Asunto(s)
Vivienda para Animales , Hipoxia/sangre , Hipoxia/psicología , Ventilación , Amoníaco/análisis , Crianza de Animales Domésticos , Animales , Recuento de Células Sanguíneas , Peso Corporal/fisiología , Dióxido de Carbono/análisis , Enfermedad Crónica , Ingestión de Líquidos/fisiología , Ingestión de Alimentos/fisiología , Conducta Exploratoria/fisiología , Humedad , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/fisiología , Oxígeno/análisis , Reconocimiento en Psicología/fisiología , Conducta Social , Natación/psicología , Gusto/fisiología
12.
Artículo en Inglés | MEDLINE | ID: mdl-35206312

RESUMEN

While the fire service has long been a male-dominated occupation, women's participation in this strenuous, high risk, high performance activity has increased in recent years. Firefighting induces significant cardiovascular strain, including hemostatic disruption; however, the effect of sex on hemostatic responses has not been investigated despite evidence that there are sex-related differences in hemostatic variables at rest and following exercise. Thus, we investigated hemostatic responses in age- and BMI-matched male and female firefighters who performed 3-4 evolutions of firefighting drills over a 3 h period. Venous blood samples were collected before and after the firefighting training drills and hemostatic variables were assessed. Firefighting significantly increased platelet count and factor VIII, tissue plasminogen activator (t-PA) antigen, and t-PA activity, and decreased activated partial thromboplastin time and plasminogen activator inhibitor (PAI-1) activity. Females had lower values for epinephrine-induced platelet closure time, antithrombin III, PAI-1 activity, and PAI-1 antigen. There were no interactions between sex and time for any variables assessed. In conclusion, multiple bouts of firefighting activity resulted in a procoagulatory state. Although there were sex differences for several hemostatic variables, male and female firefighters did not differ in their hemostatic response to multiple bouts of firefighting.


Asunto(s)
Hemostáticos , Coagulación Sanguínea/fisiología , Femenino , Fibrinólisis/fisiología , Hemostáticos/farmacología , Humanos , Masculino , Ocupaciones , Activador de Tejido Plasminógeno
13.
Prehosp Emerg Care ; 15(2): 233-9, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21366433

RESUMEN

BACKGROUND: The leading cause of line-of-duty death among firefighters is sudden cardiac events. Platelets play a critical role in the formation of an occlusive thrombus during an ischemic event. OBJECTIVE: The purpose of this study was to examine the acute effect of firefighting on platelet number and aggregability. METHODS: Apparently healthy male firefighters (N = 114; age 29.4 ± 7.8 years) participated in 18 minutes of simulated firefighting activity in a training structure that contained live fires. Blood samples were obtained before and after simulated firefighting activity and analyzed for complete blood cell count (CBC), chemistry, and platelet number and function. Platelet function was measured using a PFA-100 analyzer to assess platelet aggregability. RESULTS: As expected, performing firefighting activity resulted in significant increases in heart rate (75 b·min(-1)) and core temperature (0.7 °C), and significant changes in blood chemistry values. The most important finding in this study is that 18 minutes of simulated firefighting caused a 24% increase in platelet number and a significant increase in platelet aggregability. CONCLUSIONS: Firefighting resulted in a significant increase in platelet number and aggregability, indicating that even short bouts of firefighting can increase thrombotic potential in apparently healthy firefighters.


Asunto(s)
Plaquetas , Incendios , Calor/efectos adversos , Exposición Profesional/efectos adversos , Estrés Fisiológico , Tromboembolia/etiología , Adaptación Fisiológica , Adulto , Recuento de Células Sanguíneas , Humanos , Masculino , Consumo de Oxígeno , Pruebas de Función Plaquetaria , Factores de Riesgo
14.
Brain Behav Immun ; 24(4): 631-40, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20138982

RESUMEN

Peripheral activation of the immune system by infectious agents triggers the brain-cytokine system causing sickness behaviors which profoundly impact well-being. Dietary fiber is a beneficial foodstuff that, from a gastrointestinal tract perspective, exists in both insoluble and soluble forms. We show that a diet rich in soluble fiber protects mice from endotoxin-induced sickness behavior by polarizing mice Th2 when compared to a diet containing only insoluble fiber. Mice fed soluble fiber became less sick and recovered faster from endotoxin-induced sickness behaviors than mice fed insoluble fiber. In response to intraperitoneal endotoxin, mice fed soluble fiber had up-regulated IL-1RA and reduced IL-1beta and TNF-alpha in the brain as compared to mice fed insoluble fiber. Importantly, mice fed soluble fiber had a basal increase in IL-4 in the ileum and spleen which was absent in MyD88 knockout mice. Con-A stimulated splenocytes from mice fed soluble fiber showed increased IL-4 and IL-5 and decreased IL-2, IL-12 and IFN-gamma when compared to mice fed insoluble fiber. Likewise, endotoxin-stimulated macrophages from mice fed soluble fiber demonstrated decreased IL-1beta, TNF-alpha, IFN-gamma, IL-12 and nitrate and increased IL-1RA, arginase 1 and Ym1 when compared to mice fed insoluble fiber. Finally, the behavioral protection afforded by feeding mice soluble fiber was reduced in IL-4 knockout mice, as was the impact of soluble fiber on Con-A stimulated splenocytes and endotoxin activated macrophages. These data show that a diet rich in soluble fiber protects against endotoxin-induced sickness behavior by polarizing mice Th2 and promoting alternative activation of macrophages.


Asunto(s)
Citocinas/metabolismo , Dietoterapia/métodos , Fibras de la Dieta/farmacología , Endotoxinas/farmacología , Conducta de Enfermedad , Interleucina-4/metabolismo , Células Th2/metabolismo , Animales , Antidiarreicos/farmacología , Citocinas/genética , Citocinas/inmunología , Fibras de la Dieta/clasificación , Endotoxinas/administración & dosificación , Ensayo de Inmunoadsorción Enzimática , Íleon/citología , Íleon/efectos de los fármacos , Íleon/inmunología , Inyecciones Intraperitoneales , Interferón gamma/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Interleucina-4/deficiencia , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-6/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/deficiencia , Factor 88 de Diferenciación Mieloide/genética , Pectinas/farmacología , Reacción en Cadena de la Polimerasa , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inervación , Células Th2/efectos de los fármacos , Células Th2/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba
15.
Metabolism ; 102: 153989, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31697963

RESUMEN

BACKGROUND: Diets that include some aspect of fasting have dramatically increased in popularity. In addition, fasting reduces inflammasome activity in the brain while improving learning. Here, we examine the impact of refeeding a low-fat diet (LFD) or high-fat diet (HFD) after fasting. METHODS: Male wildtype (WT), caspase-1 knockout (KO) and/or IL-1 receptor 1 (IL-1R1) KO mice were fasted for 24 h or allowed ad libitum access to food (chow). Immediately after fasting, mice were allowed to refeed for 2 h in the presence of LFD, HFD or chow. Mouse learning was examined using novel object recognition (NOR) and novel location recognition (NLR). Caspase-1 activity was quantified in the brain using histochemistry (HC) and image analysis. RESULTS: Refeeding with a HFD but not a LFD or chow fully impaired both NOR and NLR. Likewise, HFD when compared to LFD refeeding increased caspase-1 activity in the whole amygdala and, particularly, in the posterior basolateral nuclei (BLp) by 2.5-fold and 4.6-fold, respectively. When caspase-1 KO or IL-1R1 KO mice were examined, learning impairment secondary to HFD refeeding did not occur. Equally, administration of n-acetylcysteine to fasted WT mice prevented HFD-dependent learning impairment and caspase-1 activation in the BLp. Finally, the free-fatty acid receptor 1 (FFAR1) antagonist, DC260126, mitigated learning impairment associated with HFD refeeding while blocking caspase-1 activation in the BLp. CONCLUSIONS: Consumption of a HFD after fasting impairs learning by a mechanism that is dependent on caspase-1 and the IL-1R1 receptor. These consequences of a HFD refeeding on the BLP of the amygdala appear linked to oxidative stress and FFAR1.


Asunto(s)
Encéfalo/metabolismo , Caspasa 1/metabolismo , Dieta Alta en Grasa , Ayuno/fisiología , Aprendizaje/fisiología , Animales , Peso Corporal , Encéfalo/enzimología , Activación Enzimática , Conducta Alimentaria/fisiología , Discapacidades para el Aprendizaje/etiología , Discapacidades para el Aprendizaje/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Obesidad/complicaciones , Obesidad/genética , Obesidad/psicología , Receptores Tipo I de Interleucina-1/genética
16.
Brain Behav Immun ; 23(2): 169-75, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18854211

RESUMEN

Individuals affected by hypoxia experience a variety of immune-associated sickness symptoms including malaise, fatigue, lethargy and loss of interest in the physical and social environment. Recently, we demonstrated that the interleukin (IL)-1beta arm of the neuroimmune system was critical to the sickness symptoms caused by hypoxia, and that IL-1 receptor antagonist (IL-1RA), IL-1beta's endogenous inhibitor, was critical to promoting sickness recovery. Here, we report that leptin is key to recovery from hypoxia because it dramatically augmented IL-1RA production in mice. We found that hypoxia increased leptin in white adipose tissue (WAT) which in turn, caused a marked rise in serum IL-1RA. Interestingly, in-vitro, leptin was a more potent inducer of IL-RA, in macrophages, than hypoxia. In leptin receptor defective (db/db) and leptin deficient (ob/ob) mice, sickness recovery from hypoxia was delayed 3-fold. Importantly, in ob/ob mice, leptin administration completely reversed this delayed recovery and induced a marked increase in serum IL-1RA. Finally, leptin administration to normal mice reduced hypoxia recovery time by 1/3 and dramatically increased WAT and serum IL-1RA. Leptin did not alter recovery from hypoxia in IL-1RA knock out mice. These results show that by enhancing IL-1RA production leptin promoted sickness recovery from hypoxia.


Asunto(s)
Conducta Animal/fisiología , Hipoxia/inmunología , Hipoxia/fisiopatología , Proteína Antagonista del Receptor de Interleucina 1/biosíntesis , Leptina/farmacología , Leptina/fisiología , Tejido Adiposo Blanco/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática/métodos , Hipoxia/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/sangre , Proteína Antagonista del Receptor de Interleucina 1/inmunología , Interleucina-1beta/inmunología , Interleucina-1beta/fisiología , Leptina/sangre , Macrófagos/inmunología , Macrófagos/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Movimiento/efectos de los fármacos , Movimiento/fisiología , Receptores de Leptina/deficiencia , Receptores de Leptina/genética , Factores de Tiempo
17.
Curr Opin Behav Sci ; 28: 20-24, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31667204

RESUMEN

Psychoneuroimmunology (PNI) aims to elucidate mechanisms by which the immune system can influence behavior. Given the complexity of the brain, studies using inbred rodents have shed critical insight into the presumed vagaries of the human condition. This is particularly true for stress modeling where adverse stimuli, conditions and/or interactions elicit patterned behavioral reactions that can translate across species. As example, sickness behaviors are as easily recognized in mice as they are in humans, and a family pet. Recently, nutrition has gained prominence as a regulator of brain function. Once perceived as mostly a peripheral player, except when manifest at extremes like starvation or gluttony, nutritional and/or metabolic stress is now recognized as a worrisome contributor to poor mental health especially in those who suffer from food insecurity or overnutrition. In this review, we will explore emerging areas of rodent research that demonstrate the impact of nutritional status on the stressed brain. Our overall goal is to implicate inflammasome activation as a critical convergence point for stress and nutritional dysregulation. In doing so, we will present results from studies focused on macronutrient, micronutrient and dietary bioactives so as to encourage innovative investigation into the emerging field of nutritional PNI.

18.
J Neurosci ; 27(5): 1161-6, 2007 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-17267571

RESUMEN

Acute hypoxia is experienced in an array of ailments and conditions, including asthma, chronic obstructive pulmonary disease, heart failure, sleep apnea, acute hypotension, and blast lung injury. Classically, infection activates the neuroimmune system, causing loss of interest in the social environment. We report that the non-infectious stimulus acute hypoxia triggers neuroimmune system activation (NSA), causing loss of interest in the social environment, and that recovery from hypoxia-induced NSA is impaired in a mouse model of type 2 diabetes. Importantly, recovery from the behavioral consequences of hypoxia-induced NSA was nearly ablated in MyD88 (myeloid differentiation factor 88) knock-out mice and in mice intracerebroventricularly administered the caspase-1 inhibitor ac-YVAD-CMK (ac-Tyr-Val-Asp-2,6-dimethylbenzoyloxymethylketone). Diabetic mice had prolonged recovery from NSA that could be halved by administration of subcutaneous interleukin-1 (IL-1) receptor antagonist (RA). These results show that acute hypoxia activates the IL-1beta arm of the neuroimmune system, which diabetes exacerbates and treatment with IL-1RA ameliorates.


Asunto(s)
Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Hipoxia Encefálica/inmunología , Hipoxia Encefálica/metabolismo , Neuroinmunomodulación/fisiología , Animales , Diabetes Mellitus Tipo 2/fisiopatología , Hipoxia Encefálica/fisiopatología , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Factores de Tiempo
19.
Neuroscientist ; 14(3): 235-9, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18000066

RESUMEN

Acute hypoxia is experienced by a variety of individuals (neonates to the elderly) and in an assortment of conditions and diseases (terrorist bomb attack to decompensated heart failure). Increasingly, elaboration of inflammatory cytokines appears key to the brain-based response to hypoxia, as evidenced by the biobehaviors of malaise, fatigue, lethargy, and loss of interest in the physical and social environment. These sickness symptoms implicate hypoxia-dependent activation of the neuroimmune system as a key component of acute hypoxia. Type 2 diabetes (T2D) is associated with increased incidence, severity, and delayed recovery from hypoxic events. Why T2D negatively affects acute hypoxia is not well understood. Recent work, however, reveals that anti-inflammatory pathways tied to the interleukin (IL)-1beta arm of the neuroimmune system may be critical. In this review, the authors examine the link between acute hypoxia, T2D, and neuroimmunity.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Diabetes Mellitus Tipo 2/inmunología , Encefalitis/inmunología , Hipoxia Encefálica/inmunología , Neuroinmunomodulación/inmunología , Animales , Enfermedades Autoinmunes del Sistema Nervioso/metabolismo , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Encefalitis/metabolismo , Encefalitis/fisiopatología , Humanos , Hipoxia Encefálica/metabolismo , Hipoxia Encefálica/fisiopatología , Interleucina-1beta/inmunología , Leptina/inmunología , Leptina/metabolismo , Transducción de Señal/inmunología
20.
BMC Immunol ; 9: 42, 2008 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-18667079

RESUMEN

BACKGROUND: Macrophages (MPhis) utilize macropinocytosis to integrate immune and metabolic signals in order to initiate an effective immune response. Diabetes is characterized by metabolic abnormalities and altered immune function. Here we examine the influence of diabetes on macropinocytosis in primary mouse macrophages and in an in vitro diabetes model. RESULTS: The data demonstrate that peritoneal MPhis from diabetic (db/db) mice had reduced macropinocytosis when compared to MPhis from non-diabetic (db/+) mice. Additionally, MPhis cultured in hyperglycemic conditions were less adept at macropinocytosis than those cultured in low glucose. Notably, AMP-activated protein kinase (AMPK) activity was decreased in MPhis cultured in hyperglycemic conditions. Activation of AMPK with leptin or 5-aminoimidazole-4-carboxamide-1-beta-riboside (AICAR) increased macropinocytosis and inhibition of AMPK with compound C decreased macropinocytosis. CONCLUSION: Taken together, these findings indicate that MPhis from diabetic mice have decreased macropinocytosis. This decrease appears dependent on reduced AMPK activity. These results demonstrate a previously unrealized role for AMPK in MPhis and suggest that increasing AMPK activity in diabetic MPhis could improve innate immunity and decrease susceptibility to infection.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/inmunología , Activación de Macrófagos/efectos de los fármacos , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Pinocitosis/inmunología , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/inmunología , Glucosa/deficiencia , Glucosa/inmunología , Glucosa/farmacología , Hiperglucemia/inmunología , Inmunidad/efectos de los fármacos , Leptina/farmacología , Activación de Macrófagos/inmunología , Ratones , Pinocitosis/efectos de los fármacos , Pirazoles/farmacología , Pirimidinas/farmacología , Ribonucleósidos/farmacología
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