RESUMEN
Transient suppression of peripheral immunity is a major source of complication for patients suffering from ischemic stroke. The release of Arginase I (ArgI) from activated neutrophils has recently been associated with T-cell dysfunction in a number of pathologies. However, this pathway has not been previously explored in ischemic stroke. Using the murine model of transient middle cerebral artery occlusion, we explored effects of stroke on peripheral T-cell function and evaluated the role of neutrophils and ArgI. Stimulation of splenic T cells from post-stroke animals with anti-CD3/CD28 resulted in decreased proliferation and interferon-γ production when compared with sham-surgery controls. Flow cytometric analysis of intrasplenic leukocytes exposed the presence of a transient population of activated neutrophils that correlated quantitatively with elevated ArgI levels in culture media. In vitro activation of purified resting neutrophils from unmanipulated controls confirmed the capacity for murine neutrophils to release ArgI from preformed granules. We observed decreased expression of the L-arg-sensitive CD3ζ on T cells, consistent with decreased functional activity. Critically, L-arg supplementation restored the functional response of post-stroke T cells to mitogenic stimulation. Together, these data outline a novel mechanism of reversible, neutrophil-mediated peripheral immunosuppression related to ArgI release following ischemic stroke.
Asunto(s)
Arginasa/metabolismo , Tolerancia Inmunológica , Activación Neutrófila , Neutrófilos/enzimología , Accidente Cerebrovascular/enzimología , Animales , Arginasa/sangre , Arginina/farmacología , Infarto de la Arteria Cerebral Media/parasitología , Masculino , Ratones , Ratones Endogámicos C57BL , Bazo/citología , Bazo/patología , Accidente Cerebrovascular/patología , Linfocitos TRESUMEN
Ischemic stroke is confounded by conditions such as atherosclerosis, diabetes, and infection, all of which alter peripheral inflammatory processes with concomitant impact on stroke outcome. The majority of the stroke patients are elderly, but the impact of interactions between aging and inflammation on stroke remains unknown. We thus investigated the influence of age on the outcome of stroke in animals predisposed to systemic chronic infection. Th1-polarized chronic systemic infection was induced in 18-22 month and 4-month-old C57BL/6j mice by administration of Trichuris muris (gut parasite). One month after infection, mice underwent permanent middle cerebral artery occlusion and infarct size, brain gliosis, and brain and plasma cytokine profiles were analyzed. Chronic infection increased the infarct size in aged but not in young mice at 24 h. Aged, ischemic mice showed altered plasma and brain cytokine responses, while the lesion size correlated with plasma prestroke levels of RANTES. Moreover, the old, infected mice exhibited significantly increased neutrophil recruitment and upregulation of both plasma interleukin-17α and tumor necrosis factor-α levels. Neither age nor infection status alone or in combination altered the ischemia-induced brain microgliosis. Our results show that chronic peripheral infection in aged animals renders the brain more vulnerable to ischemic insults, possibly by increasing the invasion of neutrophils and altering the inflammation status in the blood and brain. Understanding the interactions between age and infections is crucial for developing a better therapeutic regimen for ischemic stroke and when modeling it as a disease of the elderly.
Asunto(s)
Envejecimiento/fisiología , Lesiones Encefálicas/etiología , Isquemia Encefálica/patología , Isquemia Encefálica/parasitología , Tricuriasis/patología , Trichuris/crecimiento & desarrollo , Animales , Lesiones Encefálicas/inmunología , Lesiones Encefálicas/parasitología , Lesiones Encefálicas/patología , Isquemia Encefálica/inmunología , Quimiocina CCL2/metabolismo , Enfermedad Crónica , Citocinas/sangre , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos/metabolismo , Infarto de la Arteria Cerebral Media/parasitología , Infarto de la Arteria Cerebral Media/patología , Inflamación/inmunología , Inflamación/parasitología , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/patología , Distribución Aleatoria , Tricuriasis/inmunología , Regulación hacia ArribaRESUMEN
To determine whether Toxoplasma gondii infection could modify biological phenomena associated with brain ischemia, we investigated the effect of permanent middle cerebral artery occlusion (MCAO) on neuronal survival, inflammation and redox state in chronically infected mice. Infected animals showed a 40% to 50% decrease of infarct size compared with non-infected littermates 1, 4 and 14 days after MCAO. The resistance of infected mice may be associated with increased basal levels of anti-inflammatory cytokines and/or a marked reduction of the MCAO-related brain induction of two pro-inflammatory cytokines, tumor necrosis factor-alpha and interferon-gamma (IFNgamma). In addition, potential anti-inflammatory/neuroprotective factors such as nerve growth factor, suppressor of cytokine signaling-3, superoxide dismutase activity, uncoupling protein-2 and glutathione (GSH) were upregulated in the brain of infected mice. Consistent with a role of GSH in central cytokine regulation, GSH depletion by diethyl maleate inhibited Toxoplasma gondii lesion resistance by increasing the proinflammatory cytokine IFNgamma brain levels. Overall, these findings indicate that chronic toxoplasmosis decisively influences both the inflammatory molecular events and outcome of cerebral ischemia.
Asunto(s)
Isquemia Encefálica , Infarto de la Arteria Cerebral Media , Toxoplasma , Toxoplasmosis/inmunología , Toxoplasmosis/patología , Animales , Encéfalo/inmunología , Encéfalo/parasitología , Encéfalo/patología , Isquemia Encefálica/inmunología , Isquemia Encefálica/parasitología , Isquemia Encefálica/patología , Enfermedad Crónica , Citocinas/metabolismo , Glutatión/metabolismo , Hiperfagia/inmunología , Hiperfagia/parasitología , Hiperfagia/patología , Infarto de la Arteria Cerebral Media/inmunología , Infarto de la Arteria Cerebral Media/parasitología , Infarto de la Arteria Cerebral Media/patología , Canales Iónicos/genética , Masculino , Ratones , Proteínas Mitocondriales/genética , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/parasitología , Degeneración Nerviosa/patología , ARN Mensajero/metabolismo , Superóxido Dismutasa/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteína Desacopladora 2 , Regulación hacia ArribaRESUMEN
Neurocysticercosis is the most common parasitic infection of the central nervous system. Neurovascular complications have been recognized as a frequent complication, with up to 10% of strokes in endemic areas being secondary to neurocysticercosis. We report a case of acute transient left hemichorea in an 11-year-old boy with cerebral cysticercosis involving the right middle cerebral artery. Brain magnetic resonance imaging (MRI) revealed T(2)-weighted hyperintensity and gadolinium enhancement in the area surrounding the M1 segment of the right middle cerebral artery. Magnetic resonance angiography showed severe narrowing of the vessel at this site acutely. After treatment with a 1-month course of oral prednisone and initiation of aspirin, our patient had no recurrence of abnormal movements and follow-up magnetic resonance angiography and transcranial Doppler ultrasonography showed resolution of stenosis of the M1 segment.
Asunto(s)
Infarto de la Arteria Cerebral Media/diagnóstico , Infarto de la Arteria Cerebral Media/parasitología , Arteria Cerebral Media/patología , Arteria Cerebral Media/parasitología , Neurocisticercosis/complicaciones , Prednisona/administración & dosificación , Antiinflamatorios/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Aspirina/administración & dosificación , Niño , Corea/tratamiento farmacológico , Corea/parasitología , Corea/patología , Gadolinio , Humanos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Masculino , Arteria Cerebral Media/diagnóstico por imagen , Resultado del Tratamiento , Ultrasonografía Doppler TranscranealRESUMEN
Stroke is a very uncommon complication of hydatic disease. The case of a pediatric patient who suffered cerebral infarction due to the occlussion of the right middle cerebral artery, and who subsequently developed multiple hydatic cysts in the territory of the occluded vessel, is presented. Even though the diagnostic tests aimed to detect a primary focus of the disease were negative, the existing data support the possibility of a cardiac embolic origin.