RESUMO
Cannabidiol (CBD) is a highly lipidic phytocannabinoid with remarkable anti-inflammatory effects. The aim of this study was to evaluate CBD's effects and mechanisms of action in the treatment of mice subjected to acute graft-versus-host disease (aGVHD). aGVHD was induced by the transplantation of bone marrow cells and splenocytes from C57BL-6j to Balb-c mice. The recipient mice were treated daily with CBD, and the treatment reduced mouse mortality by decreasing inflammation and injury and promoting immune regulation in the jejunum, ileum, and liver. Analysis of the jejunum and ileum showed that CBD treatment reduced the levels of C-C motif chemokine ligand (CCL) 2, CCL3, CCL5, tumor necrosis factor α, and interferon γ (IFNγ). CCL3 and IFNγ levels were also decreased in the liver. Mechanistically, CBD also increased the number of cannabinoid receptor type 2 (CB2) receptors on CD4+ and forkhead box P3+ cells in the intestine, which may explain the reduction in proinflammatory cytokines and chemokines. Antagonists of the CB2 receptor reduced the survival rates of CBD-treated mice, suggesting the participation of this receptor in the effects of CBD. Furthermore, treatment with CBD did not interfere with the graft-versus-leukemia response. CBD treatment appears to protect aGVHD mice by anti-inflammatory and immunomodulatory effects partially mediated by CB2 receptor interaction. Altogether, our study suggests that CBD represents an interesting approach in the treatment of aGVHD, with potential therapeutic applications in patients undergoing bone marrow transplantation. SIGNIFICANCE STATEMENT: This study provides for the first time a mechanism by which cannabidiol, a phytocannabinoid with no psychoactive effect, induces immunomodulation in the graft-versus-host disease. Enhancing intestinal cannabinoid receptor type 2 (CB2) receptor expression on CD4+ and forkhead box P3+ cells and increasing the number of these regulatory cells, cannabidiol decreases proinflammatory cytokines and increases graft-versus-host disease mice survival. This effect is dependent of CB2 receptor activation. Besides, cannabidiol did not interfere with graft-versus-leukemia response, a central response to avoid primary disease relapse.
Assuntos
Canabidiol/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Mucosa Intestinal/metabolismo , Leucemia/terapia , Receptor CB2 de Canabinoide/metabolismo , Animais , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Canabidiol/farmacologia , Células Cultivadas , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Leucemia/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/genética , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Ischemic stroke represents a major cause of adult death and severe neurological disability worldwide. Reperfusion following brain ischemia produces an inflammatory cascade that increases brain damage. In this context, matrix metalloproteinases (MMPs) play an important role as pro-inflammatory mediators. The MMP 2 up-regulation seems to promote matrix degradation, blood-brain barrier (BBB) disruption and facilitates the influx of peripheral inflammatory cells to the brain after stroke. However, there are not studies about MMP-1 in this condition. The aim of this study is to evaluate the association of brain damage, inflammatory response and the immunostaining profile of matrix metalloproteinases 1 and 2 after transient global cerebral ischemia. Mice were submitted to bilateral common carotid arterial occlusion (BCCAo) during 25 min. After three days of reperfusion, the neurological deficit score was evaluated and the animals were euthanized. Brain samples were collected in order to analyze the histopathological damage, MMPs 1 and 2 immunostaining and cytokines and chemokines levels. Ischemic group showed neurological deficits associated with brain lesions, characterized by necrotic core and penumbra zone three days after reperfusion. Higher brain immunostaining of MMP-1 and MMP-2 was observed in BCCAo samples than in sham samples. Ischemic group also exhibited increased brain levels of the cytokines tumoral necrosis factor (TNF) and interleukin 1ß (IL-1ß), chemokine (C-X-C motif) ligand 1 (CXCL1), and chemokine (C-C motif) ligand 5 (CCL5) in comparison to sham group. Our results suggest that the MMP-1 and MMP-2 raise, associated with the up-regulation of inflammatory mediators, contributes to brain damage and neurological deficits after global brain ischemia followed by three days of reperfusion in mice.
Assuntos
Encéfalo/enzimologia , Citocinas/metabolismo , Ataque Isquêmico Transitório/enzimologia , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Quimiocina CCL5/metabolismo , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Ataque Isquêmico Transitório/patologia , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Necrose , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Regulação para CimaRESUMO
Inflammation plays a pivotal role in temporal lobe epilepsy (TLE) pathophysiology. IL-33 can act as a transcription factor or as a cytokine, the latter through the transmembrane ST2 receptor or its soluble isoform (sST2), presenting a dual role in neurological diseases. The aim of this study was to determine the plasma levels of IL-33 and sST2 in parallel with clinical features in patients with TLE. Peripheral blood from patients and controls was sampled for the measurement of plasma levels of IL-33 and sST2 by enzyme-linked immunoassay (ELISA). While there were similar levels of IL-33 between controls and patients, sST2 were increased in patients. IL33 and sST2 plasma levels were not associated with TLE-related clinical features. In a subgroup analysis, IL-33 levels correlated with memory performance. In conclusion, our results reinforce the concept of chronic low-grade inflammation in patients with TLE.
Assuntos
Epilepsia do Lobo Temporal , Citocinas , Epilepsia do Lobo Temporal/complicações , Humanos , Inflamação , Proteína 1 Semelhante a Receptor de Interleucina-1RESUMO
Hippocampal sclerosis (HS) is characterized by neuronal loss and gliosis. The intensity and distribution of these histopathological findings over the Cornu Ammonis (CA) subfields are important for the classification of HS and prognostication of patients with temporal lobe epilepsy (TLE). Several studies have associated the neuronal density reduction in the hippocampus with cognitive decline in patients with TLE. The current study aimed at investigating whether the expression of glial proteins in sclerotic hippocampi is associated with presurgical memory performance of patients with TLE. Before amygdalohippocampectomy, patients were submitted to memory tests. Immunohistochemical and morphometric analyses with glial fibrillary acidic protein (GFAP) for astrogliosis and human leucocyte antigen DR (HLA-DR) for microgliosis were performed in paraffin-embedded HS and control hippocampi. Sclerotic hippocampi exhibited increased gliosis in comparison with controls. In patients with TLE, the area and intensity of staining for HLA-DR were associated with worse performance in the memory tests. Glial fibrillary acidic protein was neither associated nor correlated with memory test performance. Our data suggest association between microgliosis, but not astrogliosis, with visual memory decline in patients with TLE.
Assuntos
Epilepsia do Lobo Temporal/psicologia , Gliose/psicologia , Hipocampo/patologia , Transtornos da Memória/psicologia , Adulto , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/psicologia , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/cirurgia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/complicações , Antígenos HLA-DR , Hipocampo/cirurgia , Humanos , Masculino , Transtornos da Memória/etiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Procedimentos Neurocirúrgicos , Esclerose , Fatores Socioeconômicos , Adulto JovemRESUMO
Chagas disease (CD) is a tropical zoonosis caused by the protozoan Trypanosoma cruzi. Severe autonomic dysfunction like reduced cardiac catecholamine-containing or acetylcholinesterase-positive innervation have been reported in CD. Renin-angiotensin system (RAS) seems to participate in the regulation of adrenal catecholamine secretion by adrenal medullary chromaffin cells, which might be dependent of nitric oxide (NO) pathways. To investigate the levels of RAS components in the adrenal gland during the acute infection with Y strain T. cruzi and in response to acute administration of an inhibitor of the enzyme NO synthase, L-NAME. Male Holtzman rats were inoculated intraperitoneally with Y strain T. cruzi and received L-NAME or tap water from one day before the infection until 13 or 17 days post-inoculation (dpi). The concentration of RAS molecules in the adrenal tissue was evaluated by ELISA immunoassay. Angiotensin converting enzyme 1 (ACE1) levels were significantly lower at 17 dpi when compared to 13 dpi. No significant differences were found compared with baseline, and no changes were detected in adrenal tissue levels of angiotensin converting enzyme 2 (ACE2), angiotensin II, or angiotensin-(1-7). Moreover, the treatment with L-NAME did not influence the levels of RAS components in adrenal tissue during the course of T. cruzi infection. We provided the first evidence that levels of RAS molecules change in the adrenal gland during acute phase of T. cruzi infection. Future studies are necessary to fully address the role of NO in RAS-associated adrenal gland function in CD.
Assuntos
Glândulas Suprarrenais/metabolismo , Doença de Chagas/metabolismo , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina/fisiologia , Trypanosoma cruzi/fisiologia , Animais , Modelos Animais de Doenças , Masculino , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: A persistent low-grade inflammatory state has been described in patients with temporal lobe epilepsy (TLE) in the interictal period. Adipokines are cytokines produced by the adipose tissue that can influence inflammatory response. The purpose of this study was to evaluate the plasma levels of adipokines in patients with TLE in comparison with controls. In addition, we sought to investigate whether the levels of adipokines were associated with clinical parameters in TLE. METHODS: Forty patients with TLE and 40 controls were enrolled in this study. All participants were subjected to clinical assessment that included the Mini International Neuropsychiatric Interview (MINI) and the Hamilton Depression Rating Scale (HAM-D). Peripheral blood was drawn, and plasma levels of adipokines (adiponectin, leptin, and resistin) were measured by enzyme-linked immunoassay (ELISA). RESULTS: People with TLE presented higher leptin and lower adiponectin and resistin levels in comparison with controls. The levels of these adipokines correlated negatively with illness length but not with other clinical parameters. In a binary logistic regression model, higher leptin and lower adiponectin levels remained as significant predictors of TLE diagnosis. CONCLUSIONS: These results corroborate the view that TLE is a multisystemic condition associated with low-grade inflammation.
Assuntos
Adiponectina/sangue , Epilepsia do Lobo Temporal/sangue , Epilepsia do Lobo Temporal/diagnóstico , Leptina/sangue , Resistina/sangue , Adipocinas/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Citocinas/sangue , Epilepsia do Lobo Temporal/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação PsiquiátricaRESUMO
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Experimental Autoimmune Encephalomyelitis (EAE) is the most widely used animal model for the study of MS. The Suppressor of Cytokine Signaling (SOCS) 2 protein plays a critical role in regulating the immune responses. The role of SOCS2 during EAE has not been explored. EAE was induced in WT and SOCS2-/- mice using myelin oligodendrocyte glycoprotein (MOG35-55) peptide. Brain and spinal cord were examined during the peak (day 14) and recovery phase (day 28) of the disease. SOCS2 was upregulated in the brain of WT mice at the peak and recovery phase of EAE. The development of the acute phase was slower in onset in SOCS2-/- mice and was associated with reduced number of Th1 (CD3+CD4+IFN-γ +) cells in the spinal cord and brain. However, while in WT mice, maximal clinical EAE score was followed by a progressive recovery; the SOCS2-/- mice were unable to recover from locomotor impairment that occurred during the acute phase. There was a prolonged inflammatory response (increased Th1 and decreased Th2 and T regulatory cells) in the late phase of EAE in the CNS of SOCS2-/- mice. Transplantation of bone marrow cells from SOCS2-/- into irradiated WT mice resulted in higher lethality at the early phase of EAE. Altogether, these results suggest that SOCS2 plays a dual role in the immune response during EAE. It is necessary for damage during the acute phase damage but plays a beneficial role in the recovery stage of the disease.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Western Blotting , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/genética , Feminino , Citometria de Fluxo , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Supressoras da Sinalização de Citocina/genética , Células Th1/metabolismo , Células Th17/metabolismo , Células Th2/metabolismoRESUMO
CONTEXT: Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neuronal survival, differentiation, and maturation. PURPOSE: To evaluate the levels of BDNF in the acute phase of stroke and their potential association with neurological impairment. METHODS: Patients in the acute phase of ischemic stroke were evaluated with the following clinical tools: National Institutes of Health Stroke Scale, modified Rankin scale, Gugging Swallowing Screen and Alberta Stroke Program Early CT Score. Blood samples were collected at 3 different moments of hospital stay. BDNF was measured through enzyme-linked immunosorbent assay. RESULTS: Patients who were discharged after 10 days had worse clinical outcomes and higher levels of BDNF since admission. There was correlation between BDNF levels and clinical parameters. CONCLUSION: BDNF levels were associated with clinical prognosis in the acute phase of ischemic stroke.
Assuntos
Isquemia Encefálica/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Acidente Vascular Cerebral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/fisiopatologia , Deglutição , Avaliação da Deficiência , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Prognóstico , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Regulação para CimaRESUMO
PURPOSE: Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with important impact on global health. Prebiotic and probiotic strategies are thought to be useful in the context of experimental IBD. Here, we compared the effects of preventive versus therapeutic treatment with a high fiber diet (prebiotic) in combination or not with Bifidobacterium longum (probiotic) in a murine model of chronic colitis. METHODS: Colitis was induced by adding dextran sulfate sodium (DSS) to drinking water for 6 days (acute colitis) or for 5 cycles of DSS (chronic colitis). RESULTS: Administration of the high fiber diet protected from acute colitis. Protection was optimal when diet was started 20 days prior to DSS. A 5-day pretreatment with acetate, a short-chain fatty acid, provided partial protection against acute colitis. In chronic colitis, pretreatment with the high fiber diet attenuated clinical and inflammatory parameters of disease. However, when the treatment with the high fiber diet started after disease had been established, overall protection was minimal. Similarly, delayed treatment with acetate or B. longum did not provide any protection even when the probiotic was associated with the high fiber diet. CONCLUSION: Preventive use of a high fiber diet or acetate clearly protects mice against acute and chronic damage induced by DSS in mice. However, protection is lost when therapies are initiated after disease has been established. These results suggest that any therapy aimed at modifying the gut environment (e.g., prebiotic or probiotic strategies) should be given early in the course of disease.
Assuntos
Biomarcadores/sangue , Colite/dietoterapia , Dieta , Fibras na Dieta/administração & dosagem , Acetatos/administração & dosagem , Doença Aguda , Animais , Comportamento Animal , Bifidobacterium/metabolismo , Doença Crônica , Colite/induzido quimicamente , Colo/microbiologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Ácidos Graxos Voláteis/administração & dosagem , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Prebióticos , Probióticos/administração & dosagemRESUMO
Plasmodium falciparum infection results in severe malaria in humans, affecting various organs, including the liver, spleen and brain, and resulting in high morbidity and mortality. The Plasmodium berghei ANKA (PbA) infection in mice closely recapitulates many aspects of human cerebral malaria (CM); thus, this model has been used to investigate the pathogenesis of CM. Suppressor of cytokine signaling 2 (SOCS2), an intracellular protein induced by cytokines and hormones, modulates the immune response, neural development, neurogenesis and neurotrophic pathways. However, the role of SOCS2 during CM remains unknown. SOCS2 knockout (SOCS2(-/-)) mice infected with PbA show an initial resistance to infection with reduced parasitemia and production of TNF, TGF-ß, IL-12 and IL-17 in the brain. Interestingly, in the late phase of infection, SOCS2(-/-) mice display increased parasitemia and reduced Treg cell infiltration, associated with enhanced levels of Th1 and Th17 cells and related cytokines IL-17, IL-6, and TGF-ß in the brain. A significant reduction in protective neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was also observed. Moreover, the molecular alterations in the brain of infected SOCS2(-/-) mice were associated with anxiety-related behaviors and cognition impairment. Mechanistically, these results revealed enhanced nitric oxide (NO) production in PbA-infected SOCS2(-/-) mice, and the inhibition of NO synthesis through l-NAME led to a marked decrease in survival, the disruption of parasitemia control and more pronounced anxiety-like behavior. Treatment with l-NAME also shifted the levels of Th1, Th7 and Treg cells in the brains of infected SOCS2(-/-) mice to the background levels observed in infected WT, with remarkable exception of increased CD8(+)IFN(+) T cells and inflammatory monocytes. These results indicate that SOCS2 plays a dual role during PbA infection, being detrimental in the control of the parasite replication but crucial in the regulation of the immune response and production of neurotrophic factors. Here, we provided strong evidence of a critical relationship between SOCS2 and NO in the orchestration of the immune response and development of CM during PbA infection.
Assuntos
Malária Cerebral/imunologia , Proteínas Supressoras da Sinalização de Citocina/imunologia , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Malária Cerebral/metabolismo , Malária Cerebral/parasitologia , Malária Cerebral/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Crescimento Neural/metabolismo , Plasmodium berghei/isolamento & purificação , Baço/metabolismo , Proteínas Supressoras da Sinalização de Citocina/antagonistas & inibidores , Proteínas Supressoras da Sinalização de Citocina/deficiência , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Infections caused by dermatophytes, mainly Trichophyton rubrum,are often vulnerable to relapses upon cessation of antifungal therapy, reinforcing the need of new antifungals. Aldimines have potential biological activities, but there are few reports on their antifungal profile. The aim of this study was to evaluate the antifungal activity of 2-(benzylideneamino)phenol (3A3) and 4-(benzylideneamino)phenol (3A4) against dermatophytes. We determined the minimum inhibitory concentration, minimum fungicidal concentration, time-kill curves and fractional inhibitory concentration of the combination of 3A3, 3A4 and itraconazole against a set of isolates of T. rubrum and T. interdigitale. 3A3 was tested in a murine model of dermatophytoses caused by T. rubrum, and the effect on phagocytosis was assessed. The MIC values ranged from 8 to 32 µg/mL for 3A3 and from 64 to 256 µg/mL for 3A4. The interaction between 3A3 and 3A4 with itraconazole proved to be synergistic and indifferent, respectively. 3A3 was as efficient as itraconazole in reducing the fungal burden on the skin of mice, being this effect associated with the influx of neutrophil and macrophage. Also, 3A3 was able to increase the internalization of conidia by macrophages. Altogether, our data encourage future clinical studies with 3A3 to treat dermatophytoses.
Assuntos
Antifúngicos/farmacologia , Fenol/farmacologia , Tinha/microbiologia , Trichophyton/efeitos dos fármacos , Animais , Antifúngicos/síntese química , Antifúngicos/química , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Fenol/química , Tinha/tratamento farmacológico , Trichophyton/genética , Trichophyton/isolamento & purificação , Trichophyton/fisiologiaRESUMO
Infection with Plasmodium falciparum may result in severe disease affecting various organs, including liver, spleen, and brain, resulting in high morbidity and mortality. Plasmodium berghei Anka infection of mice recapitulates many features of severe human malaria. The aryl hydrocarbon receptor (AhR) is an intracellular receptor activated by ligands important in the modulation of the inflammatory response. We found that AhR-knockout (KO) mice infected with P. berghei Anka displayed increased parasitemia, earlier mortality, enhanced leukocyte-endothelial cell interactions in the brain microvasculature, and increased inflammation in brain (interleukin-17 [IL-17] and IL-6) and liver (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]) compared to infected wild-type (WT) mice. Infected AhR-KO mice also displayed a reduction in cytokines required for host resistance, including TNF-α, IL-1ß, and IFN-γ, in the brain and spleen. Infection of AhR-KO mice resulted in an increase in T regulatory cells and transforming growth factor ß, IL-6, and IL-17 in the brain. AhR modulated the basal expression of SOCS3 in spleen and brain, and P. berghei Anka infection resulted in enhanced expression of SOCS3 in brain, which was absent in infected AhR-KO mice. These data suggest that AhR-mediated control of SOCS3 expression is probably involved in the phenotype seen in infected AhR-KO mice. This is, to our knowledge, the first demonstration of a role for AhR in the pathogenesis of malaria.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Malária/imunologia , Malária/patologia , Plasmodium berghei/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo , Proteínas Supressoras da Sinalização de Citocina/imunologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Encéfalo/imunologia , Encéfalo/patologia , Citocinas/imunologia , Citocinas/metabolismo , Deleção de Genes , Humanos , Fígado/imunologia , Fígado/patologia , Malária/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Hidrocarboneto Arílico/genética , Baço/imunologia , Proteína 3 Supressora da Sinalização de CitocinasRESUMO
Trichophyton rubrum is the main etiological agent of dermatophytosis, an infection of the skin that affects millions of people worldwide. In this study, we developed a murine model of the dermatophytosis caused by T. rubrum in which C57BL/6 wild-type, interleukin (IL)-12(-/-), and interferon-gamma (IFN-γ(-/-)) mice were inoculated with 1 × 10(6) conidia/animal. The fungal burden, myeloperoxidase and N-acetylglucosaminidase activities, cytokine and chemokine profiles, and histopathology of the skin were evaluated on the seventh and fourteenth days post infection. Phagocytic indices, intracellular proliferation rates, and oxidative bursts generated by macrophages from WT and IFN-γ(-/-) mice were determined. On day 7 post infection, higher fungal burdens were observed comparison with burdens on day 14 post infection. The IL-12(-/-) and IFN-γ(-/-) mice showed higher fungal burdens on the skin and lower levels of IL-1ß. Conversely, the WT mice showed lower fungal burdens with higher production of TNF-α, IL-1ß, and chemokine ligand 1/keratinocyte chemoattractant (CXCL1/KC). The macrophages from WT mice proved to be more efficient at engulfing and killing T. rubrum conidia through the production of reactive oxygen species. The results show that our model is a useful tool for understanding the pathogenesis of dermatophytosis caused by T. rubrum and that IL-12 and IFN-γ are pivotal in controlling the infection through the recruitment and activation of neutrophils and macrophages.
Assuntos
Interferon gama/metabolismo , Interleucina-1beta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tinha/imunologia , Tinha/microbiologia , Trichophyton/imunologia , Animais , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose , Pele/microbiologia , Pele/patologia , Tinha/patologiaRESUMO
Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson's disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.
Assuntos
Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Sintomas Prodrômicos , Substância Negra , Animais , Masculino , Substância Negra/metabolismo , Substância Negra/patologia , Substância Negra/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Doenças Neuroinflamatórias/patologia , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ansiedade/etiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologiaRESUMO
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.
Assuntos
Encefalite por Herpes Simples/imunologia , Encefalite por Herpes Simples/patologia , Regulação da Expressão Gênica/genética , Infiltração de Neutrófilos/fisiologia , Receptores CCR5/deficiência , Animais , Antígenos Ly/metabolismo , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/virologia , Adesão Celular/genética , Adesão Celular/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalite por Herpes Simples/genética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Leucócitos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR5/genéticaRESUMO
BACKGROUND: Paracoccidioidomycosis is the most important systemic mycosis in South America. In the last decades, it was observed that central nervous system involvement is frequent, occurring in 12.5 % of the cases. The aim of this study was to report the early inflammatory changes associated with an experimental model of neuroparacoccidioidomycosis (NPCM). METHODS: C57BL/6 mice were infected by intracranial route with 10(6) yeast cells of PB18 strain of Paracoccidioides brasiliensis. Leukocyte-endothelium interactions were assessed by intravital microscopy 1, 2, 4, and 8 weeks post-infection (p.i.). Chemokine/cytokine levels in the brain and histopathological changes were assessed 4 and 8 weeks p.i.. RESULTS: Intravital microscopy analysis revealed a progressive increase in leukocyte recruitment in the vessels of pia mater with a peak 4 weeks p.i. The chemokine CXCL9 was increased at 4 and 8 weeks p.i., while CCL2, CCL3, and CCL5 were increased at 8 weeks p.i. Histopathological analysis revealed the infiltration of inflammatory cells and the development of progressive granulomatous meningoencephalitis. CCL3 levels correlated with clinical manifestations of disease, as measured by the SHIRPA battery. CONCLUSIONS: The experimental model of NPCM showed increased leukocyte recruitment associated with increased expression of chemokines and nervous tissue inflammation which correlated with clinical manifestations of disease.
Assuntos
Infecções Fúngicas do Sistema Nervoso Central/imunologia , Infecções Fúngicas do Sistema Nervoso Central/patologia , Citocinas/biossíntese , Leucócitos/imunologia , Paracoccidioidomicose/imunologia , Paracoccidioidomicose/patologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Modelos Animais de Doenças , Histocitoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Paracoccidioides/imunologia , Paracoccidioides/isolamento & purificação , Regulação para CimaRESUMO
Hepatic encephalopathy (HE) is a potentially reversible neuropsychiatric syndrome. Often, HE causes cognitive and motor dysfunctions due to an acute or chronic insufficiency of the liver or a shunting between the hepatic portal vein and systemic vasculature. Liver damage induces peripheral changes, such as in the metabolism and peripheral inflammatory responses that trigger exacerbated neuroinflammation. In experimental models, anti-inflammatory strategies have demonstrated neuroprotective effects, leading to a reduction in HE-related cognitive and motor impairments. In this scenario, a growing body of evidence has shown that peripheral and central nervous system inflammation are promising preclinical targets. In this review, we performed an overview of FDA-approved drugs and natural compounds which are used in the treatment of other neurological and nonneurological diseases that have played a neuroprotective role in experimental HE, at least in part, through anti-inflammatory mechanisms. Despite the exciting results from animal models, the available data should be critically interpreted, highlighting the importance of translating the findings for clinical essays.
A encefalopatia hepática (EH) é uma síndrome neuropsiquiátrica potencialmente reversível. Muitas vezes a EH causa disfunções cognitivas e motoras devido à insuficiência do fígado ou por um desvio entre a veia porta hepática e a vasculatura sistêmica. O dano no fígado provoca alterações periféricas, como no metabolismo e nas respostas inflamatórias periféricas, que desencadeiam uma neuroinflamação exacerbada. Em modelos experimentais, estratégias anti-inflamatórias têm demonstrado efeitos neuroprotetores, levando a uma redução dos prejuízos cognitivos e motores relacionados à EH. Neste cenário, evidências crescentes têm mostrado a inflamação periférica e no sistema nervoso central como um promissor alvo pré-clínico. Nesta revisão, abordamos uma visão geral de drogas e compostos naturais aprovados pelo FDA para o uso no tratamento de outras doenças neurológicas e não neurológicas, que tiveram papel neuroprotetor na EH experimental, pelo menos em parte, através de mecanismos anti-inflamatórios. Apesar dos resultados empolgantes em modelos animais, os dados avaliados devem ser criticamente interpretados, destacando a importância da tradução dos achados para ensaios clínicos.
Assuntos
Encefalopatia Hepática , Fármacos Neuroprotetores , Animais , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/etiologia , Anti-Inflamatórios/uso terapêutico , Inflamação , Fármacos Neuroprotetores/uso terapêuticoRESUMO
Graft-versus-host disease (GVHD) is a serious inflammatory illness that often occurs as a secondary complication of bone marrow transplantation. Current therapies have limited effectiveness and fail to achieve a balance between inflammation and the graft-versus-tumor effect. In this study, we investigate the effects of the endocannabinoid anandamide on the complex pathology of GVHD. We assess the effects of an irreversible inhibitor of fatty acid amine hydrolase or exogenous anandamide and find that they increase survival and reduce clinical signs in GVHD mice. In the intestine of GVHD mice, treatment with exogenous anandamide also leads to a reduction in the number of CD3+, CD3+CD4+, and CD3+CD8+ cells, which reduces the activation of CD3+CD4+ and CD3+CD8+ cells, as assessed by enhanced CD28 expression, a T cell co-stimulatory molecule. Exogenous AEA was also able to reduce TNF-α and increase IL-10 in the intestine of GVHD mice. In the liver, exogenous AEA reduces injury, TNF-α levels, and the number of CD3+CD8+ cells. Interestingly, anandamide reduces Mac-1α, which lowers the adhesion of transplanted cells in mesenteric veins. These effects are mimicked by JWH133-a CB2 selective agonist-and abolished by treatment with a CB2 antagonist. Furthermore, the effects caused by anandamide treatment on survival were related to the CB2 receptor, as the CB2 antagonist abolished it. This study shows the critical role of the CB2 receptor in the modulation of the inflammatory response of GVHD by treatment with anandamide, the most prominent endocannabinoid.
Assuntos
Endocanabinoides , Doença Enxerto-Hospedeiro , Animais , Camundongos , Endocanabinoides/farmacologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Intestinos , Linfócitos/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Receptor CB1 de Canabinoide , Receptor CB2 de Canabinoide , Fator de Necrose Tumoral alfaRESUMO
Nephrotic syndrome (NS) is associated with kidney dysfunction and is an important cause of morbidity and mortality in industrialized countries. Here, we evaluated the effects of the phosphodiesterase-4 (PDE-4) inhibitors rolipram and roflumilast on a doxorubicin-induced NS model. Early-stage rolipram treatment preserved glomerular filtration barrier function, as indicated by reduced serum protein and albumin loss and the prevention of hypercholesterolemia. These effects were associated with reduced glomerular and tubular lesions and abrogated renal cell apoptosis. In addition, rolipram treatment reduced inflammation, which was characterized by a decrease in macrophage accumulation and reduced levels of CCL2 and TNF in the kidneys. Rolipram also reduced renal fibrosis, which was associated with decreased α-smooth muscle actin (α-SMA) area and increased metalloproteinase 9 (MMP9) activity in renal tissue. Late-stage rolipram or roflumilast treatment preserved glomerular filtration barrier function, as characterized by reduced serum albumin loss, decreased proteinuria, and the prevention of hypercholesterolemia. Importantly, only roflumilast treatment was associated with a reduction in glomerular and tubular lesions at this time point. In addition, both rolipram and roflumilast reduced renal tissue fibrosis and MMP9 activity in renal tissue.