RESUMEN
The most severe manifestation of Herpes Simplex Type 1 virus (HSV-1) infection is encephalitis characterized by arousal impairment and seizures that can evolve to coma and death. Previous studies reported the involvement of suppressor of cytokine signaling (SOCS) proteins, specifically SOCS1 and SOCS3, in HSV-1 infection, suggesting that other members of this family could be involved in the immune response against HSV-1. No previous study has reported the role of SOCS2 in HSV-1 infection. In the current study, C57BL/6 wild-type mice (WT) and mice deficient in SOCS2 gene (SOCS2-/-) were subjected to intracranial inoculation with 102 plaque forming units (PFU) of HSV-1. Survival curve, neuroinflammatory parameters and neuropathology were evaluated. Infected SOCS2-/- mice had increased survival in comparison with infected WT animals. This better outcome was associated with reduced leukocyte infiltration, concentration of cytokines, and structural changes in the brain. SOCS2 seems to play a detrimental role in HSV-1 encephalitis. Moreover, the control of neuroinflammatory response in HSV-1 infection was of paramount importance to clinical outcome.
Asunto(s)
Encefalitis por Herpes Simple/inmunología , Herpes Simple/inmunología , Herpesvirus Humano 1 , Proteínas Supresoras de la Señalización de Citocinas/deficiencia , Animales , Encéfalo/inmunología , Encéfalo/patología , Quimiocinas/metabolismo , Chlorocebus aethiops , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/patología , Herpes Simple/patología , Leucocitos/inmunología , Leucocitos/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Supresoras de la Señalización de Citocinas/genética , Análisis de Supervivencia , Células Vero , Carga ViralRESUMEN
Herpes simplex virus type 1 (HSV-1) is a human pathogen that may cause severe encephalitis. The exacerbated immune response against the virus contributes to the disease severity and death. Platelet activating factor (PAF) is a mediator capable of inducing increase in vascular permeability, production of cytokines on endothelial cells and leukocytes. We aimed to investigate the activation of PAF receptor (PAFR) and its contribution to the severity of the inflammatory response in the brain following HSV-1 infection. C57BL/6 wild-type (WT) and PAFR deficient (PAFR-/-) mice were inoculated intracranially with 104 plaque-forming units (PFU) of HSV-1. Visualization of leukocyte recruitment was performed using intravital microscopy. Cells infiltration in the brain tissue were analyzed by flow cytometry. Brain was removed for chemokine assessment by ELISA and for histopathological analysis. The pharmacological inhibition by the PAFR antagonist UK-74,505 was also analyzed. In PAFR-/- mice, there was delayed lethality but no difference in viral load. Histopathological analysis of infected PAFR-/- mice showed that brain lesions were less severe when compared to their WT counterparts. Moreover, PAFR-/- mice showed less TCD4+, TCD8+ and macrophages in brain tissue. This reduction of the presence of leukocytes in parenchyma may be mechanistically explained by a decrease in leukocytes rolling and adhesion. PAFR-/- mice also presented a reduction of the chemokine CXCL9 in the brain. In addition, by antagonizing PAFR, survival of C57BL/6 infected mice increased. Altogether, our data suggest that PAFR plays a role in the pathogenesis of experimental HSV-1 meningoencephalitis, and its blockade prevents severe disease manifestation.
Asunto(s)
Herpes Simple/metabolismo , Herpesvirus Humano 1 , Meningoencefalitis/metabolismo , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Glicoproteínas de Membrana Plaquetaria/deficiencia , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/deficiencia , Índice de Severidad de la Enfermedad , Animales , Encéfalo/patología , Encéfalo/virología , Dihidropiridinas/farmacología , Dihidropiridinas/uso terapéutico , Herpes Simple/patología , Herpes Simple/prevención & control , Imidazoles/farmacología , Imidazoles/uso terapéutico , Masculino , Meningoencefalitis/patología , Meningoencefalitis/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Experimental cerebral malaria (ECM) is characterized by a strong immune response, with leukocyte recruitment, blood-brain barrier breakdown and hemorrhage in the central nervous system. Phosphatidylinositol 3-kinase γ (PI3Kγ) is central in signaling diverse cellular functions. Using PI3Kγ-deficient mice (PI3Kγ-/-) and a specific PI3Kγ inhibitor, we investigated the relevance of PI3Kγ for the outcome and the neuroinflammatory process triggered by Plasmodium berghei ANKA (PbA) infection. Infected PI3Kγ-/- mice had greater survival despite similar parasitemia levels in comparison with infected wild type mice. Histopathological analysis demonstrated reduced hemorrhage, leukocyte accumulation and vascular obstruction in the brain of infected PI3Kγ-/- mice. PI3Kγ deficiency also presented lower microglial activation (Iba-1+ reactive microglia) and T cell cytotoxicity (Granzyme B expression) in the brain. Additionally, on day 6 post-infection, CD3+CD8+ T cells were significantly reduced in the brain of infected PI3Kγ-/- mice when compared to infected wild type mice. Furthermore, expression of CD44 in CD8+ T cell population in the brain tissue and levels of phospho-IkB-α in the whole brain were also markedly lower in infected PI3Kγ-/- mice when compared with infected wild type mice. Finally, AS605240, a specific PI3Kγ inhibitor, significantly delayed lethality in infected wild type mice. In brief, our results indicate a pivotal role for PI3Kγ in the pathogenesis of ECM.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ib/genética , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Malaria Cerebral/inmunología , Malaria Cerebral/patología , Plasmodium berghei/inmunología , Animales , Encéfalo/inmunología , Modelos Animales de Enfermedad , Matriz Extracelular/inmunología , Matriz Extracelular/parasitología , Femenino , Humanos , Pulmón/enzimología , Pulmón/parasitología , Malaria Cerebral/enzimología , Malaria Cerebral/parasitología , Ratones , Inhibidores de las Quinasa Fosfoinosítidos-3 , Quinoxalinas/farmacología , Análisis de Supervivencia , Tiazolidinedionas/farmacologíaRESUMEN
BACKGROUND: The neuroinflammatory response aimed at clearance of herpes simplex virus-1 (HSV-1) plays a key role in the pathogenesis of neuroaxonal damage in herpetic encephalitis. Leukocytes activated in an adaptive immune response access brain tissue by passing through the blood-brain barrier. The chemokine CCL5/RANTES is involved in recruitment of these cells to the brain acting via the receptors CCR1, CCR3 and mainly CCR5. Here, we evaluated the role of CCR5 on traffic of leukocytes in the brain microvasculature, cellular and cytokines profile in a severe form of herpetic encephalitis. RESULTS: Wild type and mice lacking CCR5 (CCR5-/-) were inoculated intracerebrally with 104 PFU of neurotropic HSV-1. We evaluated the traffic of leukocytes in the brain microvasculature using intravital microscopy and the profile of cytokines by Enzyme-Linked Immunosorbent Assay at 1 day post infection. Flow cytometry and histopathological analyses were also carried out in brain tissue. Absence of CCR5 leads to lower viral load and an increased leukocyte adhesion in brain microvasculature, predominantly of neutrophils (CD11+ Ly6G+ cells). Moreover, there was a significant increase in the levels of MIP-1/CCL2, RANTES/CCL5, KC/CXCL1 and MIG/CXCL9 in the brain of infected CCR5-/- mice. CONCLUSIONS: These results suggest that the absence of CCR5 may boost the immune response with a high neutrophil recruitment which most likely helps in viral clearance. Nonetheless, the elevated immune response may be detrimental to the host.
Asunto(s)
Encefalitis por Herpes Simple/inmunología , Encefalitis por Herpes Simple/patología , Regulación de la Expresión Génica/genética , Infiltración Neutrófila/fisiología , Receptores CCR5/deficiencia , Animales , Antígenos Ly/metabolismo , Encéfalo/inmunología , Encéfalo/patología , Encéfalo/virología , Adhesión Celular/genética , Adhesión Celular/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/genética , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Leucocitos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR5/genéticaRESUMEN
Malaria-associated lung pathology has been a neglected area in the study of malaria complications. Platelet-activating factor (PAF) is an inflammatory mediator involved in lung inflammation. Using mice lacking the PAF receptor (PAFR(-/-)) we investigated the relevance of signaling through the PAFR for the lung inflammatory process triggered by Plasmodium berghei ANKA (PbA) strain infection. In PAFR(-/-) mice, pulmonary inflammation was markedly reduced as demonstrated by histology, production of certain pro-inflammatory mediators, accumulation of macrophage and CD8+ T cells in the lung parenchyma and the virtual absence of changes in vascular permeability. Therefore, PAFR activation is crucial in the pathogenesis of pulmonary damage associated with PbA infection in C57Bl/6 mice.
Asunto(s)
Pulmón/patología , Malaria/patología , Plasmodium berghei/patogenicidad , Glicoproteínas de Membrana Plaquetaria/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Modelos Animales de Enfermedad , Histocitoquímica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Glicoproteínas de Membrana Plaquetaria/deficiencia , Receptores Acoplados a Proteínas G/deficienciaRESUMEN
The article discusses the historical, scientific and literary aspects of malaria, with an emphasis on images of the disease in the work of the writer João Guimarães Rosa. The main reference for this study is the short story "Sarapalha," which is featured in the book entitled Sagarana. The author's medical training together with his experiences in the hinterlands of the country is the subject matter for the work, with stories of the harsh reality of life in the outback. A highlight of the story is the narrative of malaria in the language of the outback, though with absolute medical and scientific precision.
RESUMEN
O artigo aborda fatores históricos, científicos e literários da malária, com ênfase nas imagens da doença na obra do escritor João Guimarães Rosa. A principal referência para este estudo é o conto "Sarapalha", presente no livro Sagarana. A formação médica do autor somada a suas experiências no interior do país serve de subsídio para a obra, com histórias vivenciadas na rudeza do sertão. Um ponto de destaque no conto é a narrativa da malária na linguagem do sertão, mas com absoluta fidedignidade médico-científica.
The article discusses the historical, scientific and literary aspects of malaria, with an emphasis on images of the disease in the work of the writer João Guimarães Rosa. The main reference for this study is the short story "Sarapalha," which is featured in the book entitled Sagarana. The author's medical training together with his experiences in the hinterlands of the country is the subject matter for the work, with stories of the harsh reality of life in the outback. A highlight of the story is the narrative of malaria in the language of the outback, though with absolute medical and scientific precision.
Asunto(s)
Humanos , Literatura , Malaria/historia , Medicina en la Literatura , Brasil , Historia Natural de las Enfermedades , FolcloreRESUMEN
Dengue virus is a human pathogen that may cause meningoencephalitis and other neurological syndromes. The current study investigated anxiety-like behavior and expression of proinflammatory cytokines and pro-apoptotic caspase-3 in the hippocampus of C57BL/6 mice infected with non-adapted Dengue virus 3 genotype I (DENV-3) inoculated intracranially with 4×10(3) (plaque-forming unit) PFU. Anxiety-like behavior was assessed in control and DENV-3 infected mice using the elevated plus maze. The open field test was performed to evaluate locomotor activity. Histopathological changes in CA regions of the hippocampus were assessed by haematoxylin and eosin staining. Immunoreactive and protein levels of cleaved caspase-3 were also analyzed in the hippocampus. The mRNA expression of IL-6 and TNF-α in the hippocampus were estimated by quantitative real time (polymerase chain reaction) PCR. All procedures were conducted on day 5 post-infection. We found that DENV-3 infected mice presented higher levels of anxiety in comparison with controls (p≤0.05). No difference in motor activity was found between groups (p=0.77). The infection was followed by a significant increase of TNF-α and IL-6 mRNA expression in the hippocampus (p≤0.05). Histological analysis demonstrated meningoencephalitis with formation of perivascular cuffs, infiltration of immune cells and loss of neurons at CA regions of hippocampus. Numerous caspase-3 positive neurons were visualized at CA areas in DENV-3 infected mice. Marked increase of cleaved caspase-3 levels were observed after infection. This study described anxiety-like behavior, hippocampal inflammation and neuronal apoptosis associated with DENV-3 infection in the central nervous system.
Asunto(s)
Trastornos de Ansiedad/etiología , Trastornos de Ansiedad/virología , Dengue/complicaciones , Encefalitis/complicaciones , Encefalitis/etiología , Animales , Apoptosis/fisiología , Virus del Dengue/genética , Virus del Dengue/patogenicidad , Virus del Dengue/fisiología , Modelos Animales de Enfermedad , Encefalitis/patología , Conducta Exploratoria/fisiología , Hipocampo/metabolismo , Hipocampo/virología , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
Cerebral malaria is a severe form of the disease that may result, in part, from an overt inflammatory response during infection by Plasmodium falciparum. The understanding of the pathogenesis of cerebral malaria may aid in the development of better therapeutic strategies for patients. The immune response in cerebral malaria involves elevation of circulating levels of cytokines and chemokines associated with leukocyte accumulation and breakdown of the blood-brain barrier in the central nervous system. Platelet-activating factor (PAF) is a mediator of inflammation shown to orchestrate inflammatory processes, including recruitment of leukocytes and increase of vascular permeability. Using mice lacking the PAF receptor (PAFR(-/-)), we investigated the relevance of this molecule for the outcome and the neuroinflammatory process triggered by P. berghei ANKA, an experimental model of cerebral malaria. In PAFR(-/-) mice, lethality was markedly delayed and brain inflammation was significantly reduced, as demonstrated by histology, accumulation, and activation of CD8(+) T cells, changes in vascular permeability and activation of caspase-3 on endothelial cells and leukocytes. Similarly, treatment with the PAFR antagonist UK-74,505 delayed lethality. Taken together, the results suggest that PAFR signaling is crucial for the development of experimental cerebral malaria. Mechanistically, PAFR activation is crucial for the cascade of events leading to changes in vascular permeability, accumulation, and activation of CD8(+) T cells and apoptosis of leukocytes and endothelial cells.
Asunto(s)
Malaria Cerebral/etiología , Glicoproteínas de Membrana Plaquetaria/fisiología , Receptores Acoplados a Proteínas G/fisiología , Animales , Química Encefálica , Caspasa 3/metabolismo , Quimiocinas/metabolismo , Citocinas/biosíntesis , Citocinas/metabolismo , Dihidropiridinas/farmacología , Imidazoles/farmacología , Leucocitos/fisiología , Activación de Linfocitos , Malaria Cerebral/prevención & control , Ratones , Ratones Endogámicos C57BL , Inhibidores de Agregación Plaquetaria/farmacología , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Glicoproteínas de Membrana Plaquetaria/deficiencia , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/deficienciaRESUMEN
Multiple sclerosis is a neuroinflammatory disease that results in serious neurological disability. Besides physical impairment, behavioral symptoms are also common in patients with multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is considered to be a model of multiple sclerosis and mimics the main features of the disease, such as demyelination and motor impairment. In this work, we aimed to study behavioral parameters in animals with EAE using the MOG35-55 model in C57BL/6 mice. We analyzed memory and anxiety in animals using the elevated plus maze, the step down inhibitory avoidance task and the memory recognition test. No differences in any tests were found when comparing controls and animals induced with EAE. Therefore, we conclude that behavioral changes in animals with EAE induced with MOG35-55 are probably subtle or absent.
Esclerose múltipla é uma doença neuroinflamatória que resulta em séria incapacidade neurológica. Além do comprometimento físico, sintomas comportamentais também são comuns em pacientes com esclerose múltipla. A encefalomielite autoimune experimental (EAE) é considerada um modelo de esclerose múltipla e mimetiza as principais caracte-rísticas da doença, como a desmielinização e a fraqueza motora. Neste trabalho, objetivamos estudar parâmetros comportamentais em animais com EAE usando o modelo de MOG35-55 em camundongos C57BL/6. Analisamos memória e ansiedade em animais utilizando o labirinto em cruz elevado, o teste da esquiva inibitória e o teste de memória de reconhecimento. Nenhuma diferença em quaisquer dos testes foi encontrada comparando animais controles e animais induzidos com EAE. Assim, concluímos que alterações comportamentais em animais com EAE induzidos com MOG35-55 são provavelmente sutis ou ausentes.
Asunto(s)
Animales , Femenino , Ratones , Ansiedad/psicología , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/psicología , Memoria/fisiología , Ansiedad/fisiopatología , Reacción de Prevención/fisiología , Encefalomielitis Autoinmune Experimental/fisiopatología , Aprendizaje por Laberinto/fisiologíaRESUMEN
Malaria is second only to tuberculosis as the leading cause of morbidity and mortality as a consequence of a single infectious agent. Much of the pathology of malaria arises from the inappropriate or excessive immune response mounted by the host in an attempt to eliminate the parasite. We here report the inflammatory changes observed in the cerebral microvasculature of C57BL/6 and BALB/c mice that had been inoculated with Plasmodium berghei NK65, a lethal strain of rodent malaria. Although no neurological signs were observed in experimentally infected mice, inflammation of the cerebral microvasculature was clearly evident. Histopathological analysis demonstrated that alterations in cerebral tissue were more intense in infected C57Bl/6 mice than in infected BALB/c animals. Intravital microscopic examination of the cerebral microvasculature revealed increased leukocyte rolling and adhesion in pial venules of infected mice compared with non-infected animals. The extravasation of Evans blue dye into the cerebral parenchyma was also elevated in infected mice in comparison with their non-infected counterparts. Additionally, protein levels of TNF-α, MIG/CXCL9, MCP-1/CCL2, MIP-1α/CCL3 and RANTES/CCL5 were up-regulated in brain samples derived from infected C57Bl/6 mice. Taken together, the data reported here illustrate the complex strain-dependent relationships between leukocyte recruitment, blood brain barrier permeability and chemokine production.
Asunto(s)
Encéfalo/inmunología , Quimiocinas/inmunología , Inflamación/inmunología , Leucocitos/inmunología , Malaria/inmunología , Plasmodium berghei/inmunología , Animales , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/metabolismo , Encéfalo/irrigación sanguínea , Permeabilidad Capilar/fisiología , Adhesión Celular/inmunología , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Femenino , Inmunohistoquímica/métodos , Leucocitos/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microscopía Fluorescente , Especificidad de la EspecieRESUMEN
Herpes simplex virus-1 (HSV-1) is a pathogen that may cause severe encephalitis in humans. In this study, we aimed to investigate the role of interleukin-4 (IL-4) in a model of HSV-1 brain infection. IL-4 knockout (IL-4-/-) and wild type (WT) C57BL/6 mice were inoculated with 10(4) plaque-forming units of HSV-1 by the intracranial route. Histopathologic analysis revealed a distinct profile of infiltrating cells at 3 days post-infection (dpi). Infected WT mice presented mononuclear inflammatory cells while IL-4-/- mice developed meningoencephalitis with predominance of neutrophils. IL-4-/- mice had diminished leukocyte adhesion at 3 dpi when compared to infected WT animals in intravital microscopy study. Conversely no differences were found in cerebral levels of CXCL1, CXCL9, CCL3, CCL5 and TNF-α between WT and IL-4-/- infected mice. IL-4 may play a role in the recruitment of cells into central nervous system in this acute model of severe encephalitis caused by HSV-1.
Asunto(s)
Quimiocinas/inmunología , Encefalitis por Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Interleucina-4/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Enfermedad Aguda , Animales , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Encefalitis por Herpes Simple/patología , Interleucina-4/fisiología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Dengue, one of the most important arboviral diseases of humans, may cause severe systemic disease. Although dengue virus (DENV) has been considered to be a non-neurotropic virus, dengue infection has been associated recently with a series of neurological syndromes, including encephalitis. In this work, we evaluated behavioral changes and inflammatory parameters in C57BL/6 mice infected with non-adapted dengue virus 3 (DENV-3) genotype I. METHODS: C57BL/6 mice received 4×10(3) PFU of DENV-3 by an intracranial route. We evaluated the trafficking of leukocytes in brain microvasculature using intravital microscopy, and evaluated chemokine and cytokine profiling by an ELISA test at 3 and 6 days post infection (p.i.). Furthermore, we determined myeloperoxidase activity and immune cell populations, and also performed histopathological analysis and immunostaining for the virus in brain tissue. RESULTS: All animals developed signs of encephalitis and died by day 8 p.i. Motor behavior and muscle tone and strength parameters declined at day 7 p.i. We observed increased leukocyte rolling and adhesion in brain microvasculature of infected mice at days 3 and 6 p.i. The infection was followed by significant increases in IFN-γ, TNF-α, CCL2, CCL5, CXCL1, and CXCL2. Histological analysis showed evidence of meningoencephalitis and reactive gliosis. Increased numbers of neutrophils, CD4+ and CD8+ T cells were detected in brain of infected animals, notably at day 6 p.i. Cells immunoreactive for anti-NS-3 were visualized throughout the brain. CONCLUSION: Intracerebral infection with non-adapted DENV-3 induces encephalitis and behavioral changes that precede lethality in mice.
Asunto(s)
Conducta Animal/fisiología , Virus del Dengue/patogenicidad , Dengue/mortalidad , Dengue/fisiopatología , Meningoencefalitis/mortalidad , Meningoencefalitis/fisiopatología , Meningoencefalitis/virología , Animales , Dengue/patología , Dengue/virología , Virus del Dengue/genética , Humanos , Masculino , Meningoencefalitis/patología , Ratones , Ratones Endogámicos C57BL , Tasa de SupervivenciaRESUMEN
Experimental autoimmune encephalomyelitis (EAE) is a condition induced in some susceptible species to the study of multiple sclerosis (MS). The platelet activating factor (PAF) is an important mediator of immune responses and seems to be involved in MS. However, the participation of PAF in EAE and MS remains controversial. Thus, in this study, we aimed to evaluate the role of PAF receptor in the pathogenesis of EAE. EAE was induced using an emulsion containing MOG(35-55). EAE-induced PAF receptor knock out (PAFR(-/-)) mice presented milder disease when compared to C57BL/6 wild type (WT) animals. PAFR(-/-) animals had lower inflammatory infiltrates in central nervous system (CNS) tissue when compared to WT mice. However, intravital microscopy in cerebral microvasculature revealed similar levels of rolling and adhering leukocytes in both WT and PAFR(-/-) mice. Interleukine (IL)-17 and chemokines C-C motif legends (CCL)2 and CCL5 were significantly lower in PAFR(-/-) mice when compared to WT mice. Brain infiltrating cluster of differentiation (CD)4(+) leukocytes and IL-17(+) leukocytes was diminished in PAFR(-/-) when compared to WT mice. Taken together, our results suggest that PAF receptor is important in the induction and development of EAE, although it has no influence in rolling and adhesion steps of cell recruitment. The absence of PAF receptor results in milder disease by altering the type of inflammatory mediators and cells that are present in CNS tissue.
Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Mediadores de Inflamación/fisiología , Leucocitos/metabolismo , Leucocitos/patología , Glicoproteínas de Membrana Plaquetaria/deficiencia , Receptores Acoplados a Proteínas G/deficiencia , Animales , Adhesión Celular/inmunología , Diferenciación Celular/fisiología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/genética , Femenino , Mediadores de Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Glicoproteínas de Membrana Plaquetaria/genética , Glicoproteínas de Membrana Plaquetaria/fisiología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiologíaRESUMEN
PURPOSE: To evaluate the effects of sepsis on brain microvasculature leukocyte rolling and adherence, myeloperoxidase (MPO) activity, cytokine and chemokine concentrations, and behavioral screening 6, 12, and 24 h after sepsis induction. METHODS: C57BL/6 mice or Wistar rats underwent cecal ligation and perforation (CLP) or sham operation. At 6, 12, and 24 h after sepsis induction, intravital microscopy was performed in the mice brain microvasculature to evaluate leukocyte rolling and adherence. Animals were killed and had the brain removed to determine MPO activity and the levels of cytokines and chemokines. A behavioral screening was also performed in a separate cohort of animals. Blood-brain barrier (BBB) permeability and cytokines and chemokines were determined in different brain regions in Wistar rats. RESULTS: There was a decrease in circulating leukocyte levels at 6, 12, and 24 h, an increase in rolling and adhesion of leukocytes in the brain microvasculature, followed by an increase in brain MPO activity. In addition, there was an increase in both brain cytokines and chemokines at different times. There was a decrease in the neuropsychiatric state muscle tone and strength only at 6 h, and a decrease in the autonomous function at 6 and 12 h. The pattern of brain cytokines and chemokines, and BBB permeability between the analyzed regions seemed to be similar with minor differences. CONCLUSIONS: During sepsis the brain's production of cytokines and chemokines is an early event and it seemed to participate both in central nervous system (CNS) dysfunction and BBB permeability alterations, reinforcing the role of brain inflammatory response in the acute CNS dysfunction associated with sepsis.
Asunto(s)
Sistema Nervioso Central/fisiopatología , Citocinas/metabolismo , Leucocitos/metabolismo , Sepsis/metabolismo , Animales , Sistema Nervioso Central/metabolismo , Delirio , Ratones , Ratones Endogámicos C57BL , Microvasos , Peroxidasa/metabolismo , Ratas , Ratas Wistar , Sepsis/fisiopatologíaRESUMEN
Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection. The underlying mechanisms of CM pathogenesis remain incompletely understood. The imbalance between the release of proinflammatory and anti-inflammatory cytokines has been associated with central nervous system dysfunction found in human and experimental CM. The current study investigated anxiety-like behavior, histopathological changes and release of brain cytokines in C57BL/6 mice infected with Plasmodium berghei strain ANKA (PbA). Anxiety-like behavior was assessed in control and PbA-infected mice using the elevated plus maze test. Histopathological changes in brain tissue were assessed by haematoxylin and eosin staining. Brain concentration of the cytokines IL-1ß, IL-4, IL-10, TNF-α and IFN-γ was determined by ELISA. We found that PbA-infected mice on day 5 post-infection presented anxiety symptoms, histopathological alterations in the brainstem, cerebrum and hippocampus and increased cerebral levels of proinflammatory cytokines IL-1ß and TNF-α. These findings suggest an involvement of central nervous system inflammatory mediators in anxiety symptoms found in CM.
Asunto(s)
Ansiedad/fisiopatología , Ansiedad/parasitología , Encéfalo/fisiopatología , Citocinas/biosíntesis , Malaria Cerebral/fisiopatología , Animales , Ansiedad/inmunología , Encéfalo/inmunología , Encéfalo/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Inflamación/parasitología , Inflamación/patología , Inflamación/fisiopatología , Malaria Cerebral/inmunología , Malaria Cerebral/patología , Ratones , Ratones Endogámicos C57BL , Plasmodium berghei/inmunologíaRESUMEN
Multiple sclerosis is a neuroinflammatory disease that results in serious neurological disability. Besides physical impairment, behavioral symptoms are also common in patients with multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is considered to be a model of multiple sclerosis and mimics the main features of the disease, such as demyelination and motor impairment. In this work, we aimed to study behavioral parameters in animals with EAE using the MOG(35-55) model in C57BL/6 mice. We analyzed memory and anxiety in animals using the elevated plus maze, the step down inhibitory avoidance task and the memory recognition test. No differences in any tests were found when comparing controls and animals induced with EAE. Therefore, we conclude that behavioral changes in animals with EAE induced with MOG(35-55) are probably subtle or absent.
Asunto(s)
Ansiedad/psicología , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/psicología , Memoria/fisiología , Animales , Ansiedad/fisiopatología , Reacción de Prevención/fisiología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BLRESUMEN
Herpes simplex virus-1 (HSV-1) is a pathogen for humans that may cause severe encephalitis. Tumor necrosis factor alpha (TNF-alpha) plays a role in several viral diseases of the central nervous system (CNS). The classic proinflammatory activities of TNF-alpha are mediated mainly through activation of the receptor 1 for TNF-alpha (TNFR1). However, when HSV-1 is inoculated in the periphery, TNF-alpha seems to protect C57Bl/6 mice against encephalitis by a mechanism independent of TNFR1. This study aims to investigate the role of TNFR1 in HSV-1 encephalitis induced by the inoculation of the virus into the brain. Wild-type C57BL/6 (WT) and TNFR1(-/-) were inoculated with 10(2) plaque-forming units of HSV-1 by the intracranial route. Infection with HSV-1 was lethal in TNFR1(-/-) mice in early times after infection. TNFR1(-/-) mice had reduced expression of the chemokines CCL3 and CCL5, and decreased leukocyte adhesion in the brain vasculature compared to WT mice 4 days post-infection (dpi). At this time point TNFR1(-/-) infected mice also had higher HSV-1 viral replication and more injuries in the brain, especially in the hippocampus. In conclusion, TNFR1 seems to play a relevant role in the control of viral replication in the CNS when HSV-1 is inoculated by intracranial route.
Asunto(s)
Encefalitis por Herpes Simple/metabolismo , Herpesvirus Humano 1 , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Animales , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Encéfalo/patología , Quimiocina CCL3/metabolismo , Quimiocina CCL5/metabolismo , Encefalitis por Herpes Simple/inmunología , Encefalitis por Herpes Simple/patología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Leucocitos/metabolismo , Leucocitos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
Experimental cerebral malaria is a neuroinflammatory condition that results from the host immune response to the parasite. Using intravital microscopy, we investigated leukocyte recruitment in the brain microcirculation and the temporal relationship of this process to the behavioral changes observed in Plasmodium berghei (strain ANKA)-infected C57Bl/6 mice. We found that leukocyte recruitment was increased from day 5 post-infection (p.i.) onwards. Histopathological changes and increased levels of inflammatory cytokines in the brain were also observed. Behavioral performance evaluated by the SHIRPA protocol showed functional impairment from day 6 p.i. onwards. Thus, early leukocyte migration into the brain and associated inflammatory changes may be involved in neurological impairment in parasite-infected C57Bl/6 mice.
Asunto(s)
Encéfalo/patología , Malaria Cerebral/patología , Malaria Cerebral/fisiopatología , Plasmodium berghei/fisiología , Acetilglucosaminidasa/metabolismo , Animales , Conducta Animal , Encéfalo/enzimología , Encéfalo/metabolismo , Encéfalo/parasitología , Quimiocinas/análisis , Macrófagos/enzimología , Malaria Cerebral/parasitología , Ratones , Ratones Endogámicos C57BL , Monocitos/enzimología , Piamadre/irrigación sanguíneaRESUMEN
The Herpes simplex virus-1 (HSV-1) is responsible for several clinical manifestations in humans, including encephalitis. To induce encephalitis, C57BL/6 mice were inoculated with 10(4) plaque-forming cells of HSV-1 by the intracranial route. Met-RANTES (regulated upon activation, normal T cell expressed and presumably secreted) (10 microg/mouse), a CC chemokine family receptor (CCR)1 and CCR5 antagonist, was given subcutaneously the day before, immediately after, and at days 1, 2, and 3 after infection. Treatment with Met-RANTES had no effect on the viral titers. In contrast, intravital microscopy revealed that treatment with Met-RANTES decreased the number of leukocytes adherent to the pial microvasculature at days 1 and 3 after infection. The levels of the chemokines CCL3, CCL5, CXCL1, and CXCL9 increased after infection and were enhanced further by the treatment with Met-RANTES. Treatment with a polyclonal anti-CCL5 antibody 2 h before the intravital microscopy decreased leukocyte adhesion in the microcirculation of infected mice. In conclusion, CCL5, a chemokine that binds to CCR1 and CCR5, is essential for leukocyte adhesion during HSV-1 encephalitis. However, blocking of CCR1 and CCR5 did not affect HSV-1 replication, suggesting that other immune mechanisms are involved in the process of infection control.