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1.
Biomed Khim ; 65(5): 380-384, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666409

RESUMO

The effects of acute (single) and chronic ethanol administration on the level of pro-inflammatory cytokines (IL-1ß and TNF-α), as well as on the level of mRNA NF-κB, TLR4 and its endogenous agonist, HMGB1 protein, were investigated in rats. It was shown that the level of TLR4, HMGB1 and cytokines was significantly higher than in control group. The ethanol withdrawal after prolonged administration resulted in dysregulation of cytokine levels, TLR4 and HMGB1. Changes in the level of TLR4 and HMGB1 mRNA demonstrated a similar pattern. The obtained data confirm that prolonged alcoholization leads to the activation of TLR4-dependent signaling in the prefrontal cortex of rats, and this can lead to a prolonged neuro-inflammatory process in the brain.


Assuntos
Alcoolismo , Encéfalo/efeitos dos fármacos , Citocinas/imunologia , Síndrome de Abstinência a Substâncias/patologia , Receptor 4 Toll-Like/imunologia , Animais , Encéfalo/imunologia , Etanol , Proteína HMGB1/metabolismo , Ratos , Transdução de Sinais , Síndrome de Abstinência a Substâncias/imunologia
2.
Psychiatr Danub ; 31(Suppl 3): 381-385, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488756

RESUMO

BACKGROUND: Psychiatric disorders may be correlated with a low-grade systemic inflammation but the origin of this inflammatory response remains unclear and both genetics and environmental factors seems to be concerned. Recent researches observed that gut microbiota seems to have an impact on the brain and immune processes. METHOD: We review recent literature to a better understanding of how microbiota interacts with brain, immunity and psychiatric disorders. We search on Pubmed, PsycINFO, PsycARTICLES and Sciencedirect articles with the keywords "gastrointestinal microbiota" and "mental disorders" or "psychological stress". RESULTS: We showed links between gut microbiota and brain-gut axis regulation, immune and endocrine system activity, neurophysiological changes, behavior variations and neuropsychiatric disorders. Communications between brain and gut are bidirectional via neural, endocrine and immune pathway. Microbiota dysbiosis and increase gut permeability with subsequent immune challenges seems to be the source of the chronic mild inflammation associated with neuropsychiatric disorders. Repeated immune or stress events early in life may lead to neurodevelopmental disorders or sickness behavior later in life. CONCLUSIONS: Psychological stress impact gut microbiota with subsequent immune activation leading to neurodevelopmental disorders or sickness behavior and altering neurophysiology and reactivity to stress or lifestyle.


Assuntos
Encéfalo/imunologia , Encéfalo/fisiopatologia , Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/fisiologia , Inflamação/imunologia , Inflamação/psicologia , Transtornos Mentais/imunologia , Transtornos Mentais/microbiologia , Disbiose/imunologia , Disbiose/microbiologia , Disbiose/psicologia , Sistema Endócrino/imunologia , Sistema Endócrino/metabolismo , Sistema Endócrino/microbiologia , Humanos , Inflamação/microbiologia , Neuropsiquiatria , Estresse Psicológico/imunologia , Estresse Psicológico/microbiologia
3.
Physiol Rev ; 99(4): 1877-2013, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31460832

RESUMO

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.


Assuntos
Bactérias/metabolismo , Encefalopatias/microbiologia , Encéfalo/microbiologia , Microbioma Gastrointestinal , Intestinos/microbiologia , Fatores Etários , Envelhecimento , Animais , Bactérias/imunologia , Bactérias/patogenicidade , Comportamento , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Encefalopatias/metabolismo , Encefalopatias/fisiopatologia , Encefalopatias/psicologia , Disbiose , Sistema Nervoso Entérico/metabolismo , Sistema Nervoso Entérico/microbiologia , Sistema Nervoso Entérico/fisiopatologia , Interações Hospedeiro-Patógeno , Humanos , Intestinos/imunologia , Neuroimunomodulação , Plasticidade Neuronal , Fatores de Risco
4.
Nat Immunol ; 20(8): 1023-1034, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263278

RESUMO

Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11b+CD45+ myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11b+CD45+ cells trafficking to ischemic brain. TREM1 inhibition genetically or pharmacologically improved outcome via protective antioxidant and anti-inflammatory mechanisms. Positron electron tomography imaging using radiolabeled antibody recognizing TREM1 revealed elevated TREM1 expression in spleen and, unexpectedly, in intestine. In the lamina propria, noradrenergic-dependent increases in gut permeability induced TREM1 on inflammatory Ly6C+MHCII+ macrophages, further increasing epithelial permeability and facilitating bacterial translocation across the gut barrier. Thus, following stroke, peripheral TREM1 induction amplifies proinflammatory responses to both brain-derived and intestinal-derived immunogenic components. Critically, targeting this specific innate immune pathway reduces cerebral injury.


Assuntos
Encéfalo/imunologia , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Acidente Vascular Cerebral/patologia , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Animais , Encéfalo/citologia , Linhagem Celular , Imunidade Inata/imunologia , Inflamação/patologia , Mucosa Intestinal/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7
6.
N Engl J Med ; 381(1): 47-54, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31269365

RESUMO

A 37-year-old man with a history of seminoma presented with vertigo, ataxia, and diplopia. An autoantibody specific for kelch-like protein 11 (KLHL11) was identified with the use of programmable phage display. Immunoassays were used to identify KLHL11 IgG in 12 other men with similar neurologic features and testicular disease. Immunostaining of the patient's IgG on mouse brain tissue showed sparse but distinctive points of staining in multiple brain regions, with enrichment in perivascular and perimeningeal tissues. The onset of the neurologic syndrome preceded the diagnosis of seminoma in 9 of the 13 patients. An age-adjusted estimate of the prevalence of autoimmune KLHL11 encephalitis in Olmsted County, Minnesota, was 2.79 cases per 100,000 men. (Funded by the Rochester Epidemiology Project and others.).


Assuntos
Autoanticorpos/análise , Encéfalo/imunologia , Proteínas de Transporte/imunologia , Técnicas de Visualização da Superfície Celular , Encefalite/imunologia , Doença de Hashimoto/imunologia , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Seminoma/complicações , Neoplasias Testiculares/complicações , Adulto , Idoso , Encefalite/epidemiologia , Doença de Hashimoto/epidemiologia , Humanos , Imunoensaio , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Prevalência
7.
PLoS Pathog ; 15(6): e1007833, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31220182

RESUMO

Rift Valley fever virus (RVFV) causes severe disease in livestock concurrent with zoonotic transmission to humans. A subset of people infected with RVFV develop encephalitis, and significant gaps remain in our knowledge of how RVFV causes pathology in the brain. We previously found that, in Lewis rats, subcutaneous inoculation with RVFV resulted in subclinical disease while inhalation of RVFV in a small particle aerosol caused fatal encephalitis. Here, we compared the disease course of RVFV in Lewis rats after each different route of inoculation in order to understand more about pathogenic mechanisms of fatal RVFV encephalitis. In aerosol-infected rats with lethal encephalitis, neutrophils and macrophages were the major cell types infiltrating the CNS, and this was concomitant with microglia activation and extensive cytokine inflammation. Despite this, prevention of neutrophil infiltration into the brain did not ameliorate disease. Unexpectedly, in subcutaneously-inoculated rats with subclinical disease, detectable viral RNA was found in the brain along with T-cell infiltration. This study sheds new light on the pathogenic mechanisms of RVFV encephalitis.


Assuntos
Encéfalo/imunologia , Encefalite Viral/imunologia , Macrófagos/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Febre do Vale de Rift/imunologia , Vírus da Febre do Vale do Rift/imunologia , Aerossóis , Animais , Encéfalo/patologia , Encéfalo/virologia , Linhagem Celular , Citocinas/imunologia , Encefalite Viral/patologia , Feminino , Humanos , Macrófagos/patologia , Neutrófilos/patologia , Ratos , Ratos Endogâmicos Lew , Febre do Vale de Rift/patologia
8.
Cell Mol Life Sci ; 76(19): 3681-3694, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31093687

RESUMO

The prominent pathological consequences of Alzheimer's disease (AD) are the misfolding and mis-sorting of two cellular proteins, amyloid-ß and microtubule-associated protein Tau. The accumulation of toxic phosphorylated Tau inside the neurons induces the increased processing of amyloid-ß-associated signaling cascade and vice versa. Neuroinflammation-driven synaptic depletion and cognitive decline are substantiated by the cross talk of activated microglia and astroglia, leading to neuron degeneration. Microglia are the brain-resident immune effectors that prove their diverse functions in maintaining CNS homeostasis via collaboration with astrocytes and T lymphocytes. Age-related senescence and chronic inflammation activate microglia with increased pro-inflammatory markers, oxidative damage and phagocytosis. But the improper processing of misfolded protein via lysosomal pathway destines the spreading of 'seed' constituents to the nearby healthy neurons. Primed microglia process and present self-antigen such as amyloid-ß and modified Tau to the infiltrated T lymphocytes through MHC I/II molecules. After an effective conversation with CD4+ T cells, microglial phenotype can be altered from pro-active M1 to neuro-protective M2 type, which corresponds to the tissue remodeling and homeostasis. In this review, we are focusing on the change in functionality of microglia from innate to adaptive immune response in the context of neuroprotection, which may help in the search of novel immune therapy in AD.


Assuntos
Doença de Alzheimer/imunologia , Apresentação do Antígeno , Microglia/imunologia , Imunidade Adaptativa , Doença de Alzheimer/terapia , Encéfalo/imunologia , Humanos , Imunoterapia , Neuroimunomodulação , Dobramento de Proteína , Linfócitos T/imunologia
9.
Acta Trop ; 196: 1-6, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31059707

RESUMO

Toxoplasmosis is a disease caused by Toxoplasma gondii, an intracellular protozoan able to infect a wide range of hosts. The infection is particularly severe in immunocompromised patients or during pregnancy, circumstances in which the parasite could find a more favorable microenvironment to replicate and invade host tissues. The current treatment consists in toxic drugs for the patients, being not appropriate for the fetuses and immunodeficient patients. So far, there is a lack of available vaccine to prevent the disease. The present study aimed to evaluate the immune response induced by peptides derived from parasite immunodominant proteins from key components, as surface, rhoptry, microneme and dense granule antigens. A panel of eleven peptides was selected considering the highest scores for B cell epitope prediction by in silico analyses. The peptides were divided in groups, according to the parasite organelle locations, and used to immunize C57BL/6 mice. The animals were submitted to three doses of immunization and infected by 10 cysts of T. gondii ME49 strain. Blood samples were collected and used to measure the production of antibodies and cytokines, while the brains were collected to determine the parasite burden by quantitative polymerase chain reaction (qPCR). It was found that synthetic peptides from all targets were able to induce IgG synthesis in immunized mice, as well as to modulate the Th1/Th2 cytokine production, particularly the MIC and SRS groups, which presented the IFN-γ/IL-10 and TNF-α/IL-10 ratios 30 and 10 times higher, respectively, when compared with non-immunized group. Interestingly, the animals from MIC and SRS groups had significantly lower levels of T. gondii DNA in their brains. In summary, it can be concluded that peptides mainly from SRS and MIC parasite components constitute relevant targets to design vaccine candidates against parasite burden observed during chronic toxoplasmosis.


Assuntos
Encéfalo/parasitologia , Epitopos Imunodominantes/imunologia , Vacinas Protozoárias/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/prevenção & controle , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Encéfalo/imunologia , Citocinas/metabolismo , Epitopos de Linfócito B/imunologia , Feminino , Imunização , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/imunologia , Proteínas de Protozoários/genética
10.
EBioMedicine ; 43: 424-434, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31085101

RESUMO

BACKGROUND: The delivery of therapeutic proteins to selected sites within the central nervous system (CNS) parenchyma is a major challenge in the treatment of various neurodegenerative disorders. As brain-derived neurotrophic factor (BDNF) is reduced in the brain of people with Alzheimer's disease (AD) and its administration has shown promising therapeutic effects in mouse model of the disease, we generated a novel platform for T cell-based BDNF delivery into the brain parenchyma. METHODS: We generated amyloid beta-protein (Aß)-specific CD4 T cells (Aß-T cells), genetically engineered to express BDNF, and injected them intracerebroventricularly into the 5XFAD mouse model of AD. FINDINGS: The BDNF-secreting Aß-T cells migrated efficiently to amyloid plaques, where they significantly increased the levels of BDNF, its receptor TrkB, and various synaptic proteins known to be reduced in AD. Furthermore, the injected mice demonstrated reduced levels of beta-secretase 1 (BACE1)-a protease essential in the cleavage process of the amyloid precursor protein-and ameliorated amyloid pathology and inflammation within the brain parenchyma. INTERPRETATION: A T cell-based delivery of proteins into the brain can serve as a platform to modulate neurotoxic inflammation and to promote neuronal repair in neurodegenerative diseases.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Biomarcadores , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Células Piramidais/imunologia , Células Piramidais/metabolismo , Células Piramidais/patologia , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
11.
Vet Immunol Immunopathol ; 211: 49-57, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084894

RESUMO

Histophilus somni is a Gram negative coccobacillus that causes respiratory, reproductive and central nervous system disease in cattle. The hallmark of H. somni infection is diffuse vasculitis and intravascular thrombosis that can lead to an acute central nervous system disease known as thrombotic meningoencephalitis (TME). Because neutrophils are major players in the pathophysiology of septic meningitis, we sought to determine their role in H. somni-induced fibrin clot formation in vitro. Bovine brain endothelial cells (TBBE cells) were exposed to H. somni cells at a 1:25 ratio, respectively. Conditioned media (CM) were collected after a 6 h incubation at 37 °C with 5% CO2, and then incubated with bovine peripheral blood polymorphonuclear neutrophils (PMNs). Following incubation, fibrin clot formation and tissue factor activity were assessed by a re-calcified plasma clotting assay. We found greater tissue factor activity in cell lysates and CM from H. somni-stimulated TBBE cells than unstimulated control TBBE cells. In addition, PMNs exposed to CM or extracellular vesicles from H. somni-stimulated TBBE cells expressed von Willenbrand factor, exhibited increased fibrin clot formation, and displayed greater tissue factor activity than PMNs exposed to CM or extracellular vesicles from unstimulated control TBBE cells. These results suggest that bovine PMNs might acquire extracellular vesicles from endothelial cells that leads to thrombus formation in bovine brain microvasculature and contribute to the process that characterizes TME.


Assuntos
Encéfalo/microbiologia , Doenças dos Bovinos/microbiologia , Células Endoteliais/microbiologia , Vesículas Extracelulares/microbiologia , Neutrófilos/imunologia , Infecções por Pasteurellaceae/veterinária , Pasteurellaceae , Animais , Encéfalo/imunologia , Bovinos , Doenças dos Bovinos/imunologia , Meios de Cultivo Condicionados , Células Endoteliais/imunologia , Vesículas Extracelulares/imunologia , Interações Hospedeiro-Patógeno/imunologia , Neutrófilos/fisiologia , Pasteurellaceae/imunologia , Infecções por Pasteurellaceae/imunologia , Trombose/imunologia , Trombose/microbiologia , Trombose/veterinária
12.
Nat Commun ; 10(1): 1667, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971685

RESUMO

Neutrophils are crucial mediators of host defense that are recruited to the central nervous system (CNS) in large numbers during acute bacterial meningitis caused by Streptococcus pneumoniae. Neutrophils release neutrophil extracellular traps (NETs) during infections to trap and kill bacteria. Intact NETs are fibrous structures composed of decondensed DNA and neutrophil-derived antimicrobial proteins. Here we show NETs in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis, and their absence in other forms of meningitis with neutrophil influx into the CSF caused by viruses, Borrelia and subarachnoid hemorrhage. In a rat model of meningitis, a clinical strain of pneumococci induced NET formation in the CSF. Disrupting NETs using DNase I significantly reduces bacterial load, demonstrating that NETs contribute to pneumococcal meningitis pathogenesis in vivo. We conclude that NETs in the CNS reduce bacterial clearance and degrading NETs using DNase I may have significant therapeutic implications.


Assuntos
Líquido Cefalorraquidiano/citologia , Armadilhas Extracelulares/microbiologia , Evasão da Resposta Imune , Meningite Pneumocócica/imunologia , Neutrófilos/imunologia , Streptococcus pneumoniae/imunologia , Adolescente , Adulto , Idoso , Animais , Grupo Borrelia Burgdorferi/imunologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/microbiologia , Líquido Cefalorraquidiano/imunologia , Líquido Cefalorraquidiano/microbiologia , Desoxirribonuclease I/administração & dosagem , Modelos Animais de Doenças , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/imunologia , Feminino , Humanos , Neuroborreliose de Lyme/líquido cefalorraquidiano , Neuroborreliose de Lyme/imunologia , Neuroborreliose de Lyme/microbiologia , Masculino , Meningite Pneumocócica/líquido cefalorraquidiano , Meningite Pneumocócica/tratamento farmacológico , Meningite Pneumocócica/microbiologia , Meningite Viral/líquido cefalorraquidiano , Meningite Viral/imunologia , Pessoa de Meia-Idade , Neutrófilos/microbiologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Punção Espinal , Streptococcus pneumoniae/isolamento & purificação , Hemorragia Subaracnóidea/líquido cefalorraquidiano , Adulto Jovem
13.
Nat Immunol ; 20(5): 559-570, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30996332

RESUMO

The C-type lectin receptor-Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans. The cytokine IL-1ß served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1ß and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1ß, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1ß and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host-pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/imunologia , Candidíase/imunologia , Quimiocina CXCL1/imunologia , Interleucina-1beta/imunologia , Microglia/imunologia , Neutrófilos/imunologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/microbiologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Candida albicans/imunologia , Candida albicans/fisiologia , Candidíase/genética , Candidíase/microbiologia , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Inflamassomos/genética , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Microglia/metabolismo , Microglia/microbiologia , Infiltração de Neutrófilos/genética , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia
14.
Psychopharmacology (Berl) ; 236(5): 1597-1609, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30997526

RESUMO

The gut microbiota is comprised of a vast variety of microbes that colonize the gastrointestinal tract and exert crucial roles for the host health. These microorganisms, partially via their breakdown of dietary components, are able to modulate immune response, mood, and behavior, establishing a chemical dialogue in the microbiota-gut-brain interphase. Changes in the gut microbiota composition and functionality are associated with multiple diseases, in which altered levels of gut-associated neuropeptides are also detected. Gut neuropeptides are strong neuroimmune modulators; they mediate the communication between the gut microbiota and the host (including gut-brain axis) and have also recently been found to exert antimicrobial properties. This highlights the importance of understanding the interplay between gut neuropeptides and microbiota and their implications on host health. Here, we will discuss how gut neuropeptides help to maintain a balanced microbiota and we will point at the missing gaps that need to be further investigated in order to elucidate whether these molecules are related to neuropsychiatric disorders, which are often associated with gut dysbiosis and altered gut neuropeptide levels.


Assuntos
Encéfalo/imunologia , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/imunologia , Neuropeptídeos/imunologia , Animais , Anti-Infecciosos/efeitos adversos , Encéfalo/metabolismo , Disbiose/induzido quimicamente , Disbiose/imunologia , Disbiose/metabolismo , Trato Gastrointestinal/metabolismo , Humanos , Neuropeptídeos/metabolismo
15.
Immunity ; 50(4): 892-906, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995505

RESUMO

The interleukin 17 (IL-17) family of cytokines contains 6 structurally related cytokines, IL-17A through IL-17F. IL-17A, the prototypical member of this family, just passed the 25th anniversary of its discovery. Although less is known about IL-17B-F, IL-17A (commonly known as IL-17) has received much attention for its pro-inflammatory role in autoimmune disease. Over the past decade, however, it has become clear that the functions of IL-17 are far more nuanced than simply turning on inflammation. Accumulating evidence indicates that IL-17 has important context- and tissue-dependent roles in maintaining health during response to injury, physiological stress, and infection. Here, we discuss the functions of the IL-17 family, with a focus on the balance between the pathogenic and protective roles of IL-17 in cancer and autoimmune disease, including results of therapeutic blockade and novel aspects of IL-17 signal transduction regulation.


Assuntos
Citocinas/imunologia , Interleucina-17/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Encéfalo/imunologia , Regulação da Expressão Gênica , Humanos , Infecção/imunologia , Inflamação/imunologia , Interleucina-17/antagonistas & inibidores , Camundongos , Terapia de Alvo Molecular , Neoplasias/imunologia , Proteínas de Ligação a RNA/imunologia , Receptores de Interleucina-17/antagonistas & inibidores , Receptores de Interleucina-17/imunologia , Transdução de Sinais , Estresse Fisiológico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Ferimentos e Lesões/imunologia
16.
J Agric Food Chem ; 67(18): 5122-5134, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30995031

RESUMO

Neuroinflammation has been intensively demonstrated to be related to various neurodegenerative diseases including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). A natural polymethoxylated flavone, nobiletin (NOB) has been reported to alleviate oxidative stress, insulin resistance, and obesity. In this study, we evaluated the protection effects of NOB on neuroinflammation and memory deficit. Three-month mice were administrated with NOB by oral gavage every day for 6 weeks (100 mg/kg/day); subsequently mice were injected intraperitoneally with lipopolysaccharide (LPS) for 7 days. Results of behavioral tests revealed that NOB dramatically ameliorated LPS-triggered memory deficit regarding synaptic dysfunctions and neuronal loss. Also, NOB suppressed the microglial activation and proinflammatory cytokine secretion, such as COX-2, IL-1ß, TNF-α, and iNOS. Similarly, upon LPS stimulation, pretreatment NOB diminished the secretion of the proinflammatory cytokines in BV-2 microglia cells by exposure to LPS via modulating MAPKs, PI3K/AKT, and NF-κB signaling pathways. In addition, NOB alleviated LPS-amplified redox imbalance, disturbance of mitochondrial membrane potential (MMP), and dampening of the expression of protein related to mitochondrial respiration. The present study provides compelling evidence that NOB decreased LPS-stimulated neuroinflammation and memory impairment through maintaining cellular oxidative balance and blocking the NF-κB transcriptional pathway, illustrating that the nutritional compound NOB may serve as a potential approach to alleviate neuroinflammation-related diseases.


Assuntos
Flavonas/administração & dosagem , Inflamação/complicações , Transtornos da Memória/prevenção & controle , Quinases de Proteína Quinase Ativadas por Mitógeno/imunologia , NF-kappa B/imunologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/genética , Transtornos da Memória/imunologia , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/imunologia , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
17.
Parasitol Int ; 71: 106-120, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30981893

RESUMO

In animal model of experimental cerebral malaria (ECM), the genesis of neuropathology is associated with oxidative stress and inflammatory mediators. There is limited progress in the development of new approaches to the treatment of cerebral malaria. Here, we tested whether oral supplementation of Coenzyme Q10 (CoQ10) would offer protection against oxidative stress and brain associated inflammation following Plasmodium berghei ANKA (PbA) infection in C57BL/6 J mouse model. For this purpose, one group of C57BL/6 mice was used as control; second group of mice were orally supplemented with 200 mg/kg CoQ10 and then infected with PbA and the third group was PbA infected alone. Clinical, biochemical, immunoblot and immunological features of ECM was monitored. We observed that oral administration of CoQ10 for 1 month and after PbA infection was able to improve survival, significantly reduced oedema, TNF-α and MIP-1ß gene expression in brain samples in PbA infected mice. The result also shows the ability of CoQ10 to reduce cholesterol and triglycerides lipids, levels of matrix metalloproteinases-9, angiopoietin-2 and angiopoietin-1 in the brain. In addition, CoQ10 was very effective in decreasing NF-κB phosphorylation. Furthermore, CoQ10 supplementation abrogated Malondialdehyde, and 8-OHDG and restored cellular glutathione. These results constitute the first demonstration that oral supplementation of CoQ10 can protect mice against PbA induced oxidative stress and neuro-inflammation usually observed in ECM. Thus, the need to study CoQ10 as a candidate of antioxidant and immunomodulatory molecule in ECM and testing it in clinical studies either alone or in combination with antimalaria regimens to provide insight into a potential translatable therapy.


Assuntos
Encéfalo/imunologia , Fatores Imunológicos/administração & dosagem , Inflamação/prevenção & controle , Malária Cerebral/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ubiquinona/análogos & derivados , Administração Oral , Animais , Encéfalo/patologia , Quimiocina CCL4/genética , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Inflamação/patologia , Malária Cerebral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fosforilação , Plasmodium berghei , Fator de Necrose Tumoral alfa/genética , Ubiquinona/administração & dosagem
18.
Microbiol Spectr ; 7(2)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30873934

RESUMO

Streptococcus pneumoniae (the pneumoccus) is the leading cause of otitis media, community-acquired pneumonia, and bacterial meningitis. The success of the pneumococcus stems from its ability to persist in the population as a commensal and avoid killing by immune system. This chapter first reviews the molecular mechanisms that allow the pneumococcus to colonize and spread from one anatomical site to the next. Then, it discusses the mechanisms of inflammation and cytotoxicity during emerging and classical pneumococcal infections.


Assuntos
Inflamação/imunologia , Inflamação/microbiologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Sangue/imunologia , Sangue/microbiologia , Encéfalo/imunologia , Encéfalo/microbiologia , Parede Celular/imunologia , Infecções Comunitárias Adquiridas/microbiologia , Orelha Média/microbiologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Feto/imunologia , Feto/microbiologia , Coração/microbiologia , Humanos , Meningites Bacterianas/microbiologia , Nasofaringe/imunologia , Nasofaringe/microbiologia , Otite Média/microbiologia , Infecções Pneumocócicas/microbiologia , Pneumonia/microbiologia , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Streptococcus pneumoniae/patogenicidade
19.
PLoS One ; 14(3): e0212313, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30840633

RESUMO

BACKGROUND: Patient-reported outcomes predict mortality and play increasingly important roles in care, but factors that modify central measures such as health ratings have been little investigated. Building on designated immune-to-brain pathways, we aimed to determine how a short-term induced inflammation response impacts self-reported health status. METHODS: Lipopolysaccharide injections were used to provoke acute systemic inflammatory responses in healthy men and women and were compared to placebo in two double-blind randomized experiments. In Experiment 1, 8 individuals (mean 24 years; SD = 3.7) received lipopolysaccharide 0.8 ng/kg once and placebo once in a cross-over design, and in Experiment 2, 52 individuals received either lipopolysaccharide 0.6 ng/kg or placebo once (28.6 years; SD = 7.1). Main outcomes were perceived health (general and current), sickness behaviour (like fatigue, pain and negative affect), and plasma interleukin-6, interleukin-8 and tumour necrosis factor-α, before and after injection. RESULTS: Compared to placebo, lipopolysaccharide lead to a deterioration in both self-rated general (Experiment 1, b = 1.88 for 0.8 ng/kg) and current health (Experiment 1 b = -3.00; and Experiment 2 b = -1.79) 1.5h after injection (p's<0.01), effects that remained after 4.5 to 5 hours (p's<0.05). The effect on current health in Experiment 2 was mediated by increased inflammation and sickness behaviour in response to lipopolysaccharide injection (ß = -0.28, p = 0.01). CONCLUSION: Health is drastically re-evaluated during inflammatory activation. The findings are consistent with notions that inflammation forms part of health-relevant interoceptive computations of bodily state, and hint at one mechanism as to why subjective health predicts longevity.


Assuntos
Imunidade/imunologia , Adulto , Encéfalo/imunologia , Estudos Cross-Over , Autoavaliação Diagnóstica , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Inflamação/sangue , Inflamação/imunologia , Interleucina-6/sangue , Interleucina-8/sangue , Lipopolissacarídeos/imunologia , Masculino , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
20.
Arch Pharm Res ; 42(5): 416-425, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30830660

RESUMO

Glial cells outnumber neurons in the brain and play important roles in the neuroinflammation that accompanies brain damage in neurodegenerative diseases. In Parkinson's disease (PD), dopaminergic neuronal loss is accompanied by inflammatory changes in microglia, astrocytes, innate immune cells, and infiltrating peripheral immune cells. Neuroinflammation is probably a fundamental immune response to protect neurons from harm and compensate for neuronal damage, but at the same time, its neurotoxic effects exacerbate neuron damage. Furthermore, neuroinflammatory response is regulated by immune cells, such as microglia, astrocytes, and peripheral immune cells, and by cytokines and chemokines. Accordingly, it is crucial that we understand how such immune cells in the brain regulate neuroinflammatory responses in PD pathology. This review describes the roles played by glia-mediated neuroinflammation in PD, both good and bad, and the therapeutic strategies used to treat PD.


Assuntos
Encéfalo/patologia , Inflamação/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/prevenção & controle , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Linfócitos/imunologia , Linfócitos/metabolismo , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/etiologia , Doença de Parkinson/imunologia , Doença de Parkinson/patologia , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Receptores Ativados por Proliferador de Peroxissomo/metabolismo
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