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1.
Int Immunopharmacol ; 73: 527-538, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31176083

RESUMO

The kynurenine pathway (KP), a major route of tryptophan catabolism, may be associated with the pathophysiology of depressive disorders. KP is responsible for ca. 99% of brain tryptophan metabolism via its degradation to kynurenine (KYN) catalyzed by indoleamine 2,3-dioxygenase (IDO). Some cytokines, such as interferon-γ (IFN-γ) and interleukin (IL)-6 are potent inducers of IDO. KYN is further converted by kynurenine aminotransferase (KAT) to the more neuroprotective kynurenic acid or by kynurenine 3-monooxygenase (KMO) to neurotoxic 3-hydroxykynurenine. The aim of the present study was to delineate whether the administration of imipramine (IMI) to rats subjected to chronic mild stress (CMS) may reverse behavioral changes induced by CMS in association with changes in immune-inflammatory markers and KP. We confirmed that the CMS procedure modeled one of the main symptoms of depression, i.e. anhedonia, and administration of IMI for 5 weeks resulted in a significant reduction in anhedonia in a majority of animals (CMS IMI-R animals), whereas 20% of animals did not respond to IMI treatment (CMS IMI-NR animals). We established that CMS procedure increased IFN-γ and IDO mRNA and decreased KAT II mRNA expression in the rat cortex. In the cortex and hippocampus, IMI treatment and non-responsiveness to IMI (in CMS IMI-NR animals) were associated with increased IL-6 mRNA expression. In the spleen, CMS increased production of IFN-γ and IL-6 proteins, while these cytokines were decreased by IMI in CMS IMI-R animals. Chronic IMI administration to CMS rats decreased IDO and KMO mRNA and protein expression and increased KAT II/KMO mRNA and protein ratio in IMI responders (CMS IMI-R) in comparison to CMS rats. In CMS IMI-NR rats, a significant increase in IDO mRNA expression and protein level in comparison with IMI responders was observed. Our findings indicate that resistance to therapeutic action of IMI could be explained by a deficiency of the inhibitory properties of IMI on IDO, KMO and KYN synthesis in the cortex. We conclude that the antidepressant activity of IMI may, at least in part, be explained by modulatory activities on the KAT II/KMO ratio in brain areas.


Assuntos
Depressão/imunologia , Resistência a Medicamentos/imunologia , Cinurenina/imunologia , Estresse Psicológico/imunologia , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Proliferação de Células , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/imunologia , Citocinas/genética , Depressão/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Imipramina/farmacologia , Imipramina/uso terapêutico , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Ratos Wistar , Baço/citologia , Estresse Psicológico/tratamento farmacológico
2.
Transl Psychiatry ; 9(1): 153, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127084

RESUMO

Genetic, epidemiological, and biomarker studies suggest that the immune system is involved in the pathogenesis of bipolar disorder (BD). It has therefore been hypothesized that immune activation of microglia, the resident immune cells of the brain, is associated with the disease. Only a few studies have addressed the involvement of microglia in BD so far and a more detailed immune profiling of microglial activation is lacking. Here, we applied a multi-level approach to determine the activation state of microglia in BD post-mortem brain tissue. We did not find differences in microglial density, and mRNA expression of microglial markers in the medial frontal gyrus (MFG) of patients with BD. Furthermore, we performed in-depth characterization of human primary microglia isolated from fresh brain tissue of the MFG, superior temporal gyrus (STG), and thalamus (THA). Similarly, these ex vivo isolated microglia did not show elevated expression of inflammatory markers. Finally, challenging the isolated microglia with LPS did not result in an increased immune response in patients with BD compared to controls. In conclusion, our study shows that microglia in post-mortem brain tissue of patients with BD are not immune activated.


Assuntos
Transtorno Bipolar/imunologia , Córtex Cerebral/imunologia , Microglia/imunologia , Tálamo/imunologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
3.
Int Immunopharmacol ; 68: 234-241, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30703695

RESUMO

The nod-like receptor protein 3 (NLRP3) inflammasome has a critical role in cerebral ischemic injury, and autophagy is related to activation of the inflammasome under oxidative stress conditions. However, it is unclear how NLRP3 inflammasome activation is regulated. Glycogen synthase kinase 3ß (GSK-3ß) emerged as an important risk factor for brain ischemia reperfusion injury, and GSK-3ß inhibits autophagic activity in many diseases. In this study, we examined whether NLRP3 inflammasome-derived inflammation could be ameliorated by GSK-3ß inhibition in a cerebral ischemia reperfusion injury model and assessed whether autophagy is involved in this process. To establish ischemic reperfusion injury, we used a middle cerebral artery occlusion-reperfusion (MCAO/R) model in rats. A chemical inhibitor (SB216763) and GSK-3ß siRNA were used to suppress GSK-3ß activation and GSK-3ß expression in vivo. The results demonstrated that SB216763 and GSK-3ß siRNA improved neurological scores, reduced cerebral infarct volume, and decreased the levels of NLRP3 inflammasome, cleaved-caspase-1, IL-1ß, and IL-18. Inhibiting GSK-3ß activation enhanced autophagic activity (ratio of LC3B-II/LC3B-I and p62/SQSTM1), whereas treating with an autophagy inhibitor (3-MA) abrogated the inhibitory effect on NLRP3 inflammasome activation after GSK-3ß inhibition. These results suggest that inhibiting GSK-3ß downregulates NLRP3 inflammasome expression by increasing autophagic activity in cerebral ischemia reperfusion injury. GSK-3ß might be an attractive specific target and that it functions by regulating the NLRP3 inflammasome.


Assuntos
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Infarto da Artéria Cerebral Média/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Traumatismo por Reperfusão/imunologia , Animais , Autofagia/efeitos dos fármacos , Córtex Cerebral/imunologia , Córtex Cerebral/patologia , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/imunologia , Indóis/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Interleucina-18/imunologia , Interleucina-1beta/imunologia , Masculino , Maleimidas/farmacologia , RNA Interferente Pequeno/administração & dosagem , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia
4.
Front Immunol ; 9: 2230, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364161

RESUMO

There is increasing evidence for the role of inflammation in schizophrenia, yet the stability of increased peripheral inflammation in acute psychosis and the degree to which peripheral inflammation relates to cortical thickness, a measure of the degree of neuropathology, are unknown. In independent samples, we assessed the peripheral inflammation marker C-reactive protein (CRP) to determine the extent to which: (1) CRP was elevated and stable across admissions for acute psychosis, (2) cognition, daily function and symptom severity are characteristic of chronically ill patients with schizophrenia displaying elevated CRP, and (3) CRP levels predict cortical thickness. Study 1 assessed peripheral CRP (primary outcome) and other blood measures in 174/280 people with acute psychosis while Study 2 assessed peripheral CRP, cognition and cortical thickness (primary outcomes), symptoms, and daily function in 85/97 chronically ill patients with schizophrenia and 71/87 healthy controls. In acute psychosis, CRP and neutrophil-to-lymphocyte ratio were significantly elevated relative to a normal cutoff (with 59.8% of patients having elevated CRP) which remained elevated across admissions. CRP was significantly elevated in 43% of chronically ill patients with schizophrenia compared to 20% in controls. Elevated CRP patients displayed significantly worse working memory and CRP was inversely correlated with cortical thickness in frontal, insula, and temporal brain regions. This work supports the role of inflammation in psychotic illnesses and suggests that use of peripheral markers (e.g., CRP) in conjunction with diagnosis could be used to identify patients with more cortical neuropathology and cognitive deficits.


Assuntos
Proteína C-Reativa/imunologia , Córtex Cerebral/imunologia , Transtornos Psicóticos/imunologia , Esquizofrenia/imunologia , Adulto , Antipsicóticos/uso terapêutico , Proteína C-Reativa/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
5.
J Neurosci ; 38(40): 8707-8722, 2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30201775

RESUMO

Microcirculatory damage is a common complication for those with vascular risk factors, such as diabetes. To resolve vascular insults, the brain's immune cells (microglia) must rapidly envelop the site of injury. Currently, it is unknown whether Type 1 diabetes, a condition associated with chronic immune system dysfunction, alters microglial responses to damage and what mechanisms are responsible. Using in vivo two-photon microscopy in adult male mice, we show that microglial envelopment of laser-induced cerebral microbleeds is diminished in a hyperglycemic mouse model of Type 1 diabetes, which could not be fully rescued with chronic insulin treatment. Microglia were important for vessel repair because reduced microglial accumulation in diabetic mice or near-complete depletion in healthy controls was associated with greater secondary leakage of the damaged vessel. Broadly suppressing inflammation with dexamethasone in diabetic mice but not healthy controls, significantly enhanced microglial responses to microbleeds and attenuated secondary vessel leakage. These enhancements were associated with changes in IFN-γ signaling because dexamethasone suppressed abnormally high levels of IFN-γ protein levels in brain and blood serum of diabetic mice. Further, blocking IFN-γ in diabetic mice with neutralizing antibodies restored normal microglial chemotaxic responses and purinoceptor P2ry12 gene expression, as well as mitigated secondary leakage. These results suggest that abnormal IFN-γ signaling disrupts microglial function in the diabetic brain, and that immunotherapies targeting IFN-γ can stimulate microglial repair of damaged vessels.SIGNIFICANCE STATEMENT Although Type 1 diabetes is an established risk factor for vascular complications, such as microbleeds, and is known to hinder wound healing in the body, no study has examined how diabetes impacts the brain's innate immune reparative response (involving cells called microglia) to vascular injury. Here we show that microglial responses to brain microbleeds were diminished in diabetic animals, which also exacerbated secondary leakage from damaged vessels. These impairments were related to abnormally high levels of the proinflammatory cytokine IFN-γ because reducing IFN-γ with immunosuppressant drugs or blocking antibodies helped restore normal microglial responses and repair of damaged vessels. These data highlight the use of IFN-γ modulating therapeutics to enhance vascular repair in at-risk populations.


Assuntos
Córtex Cerebral/imunologia , Hemorragia Cerebral/imunologia , Diabetes Mellitus Tipo 1/imunologia , Interferon gama/imunologia , Microglia/imunologia , Animais , Córtex Cerebral/irrigação sanguínea , Hemorragia Cerebral/complicações , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Modelos Animais de Doenças , Encefalite/sangue , Encefalite/complicações , Encefalite/imunologia , Masculino , Camundongos Endogâmicos C57BL , Imagem Óptica
6.
Proc Natl Acad Sci U S A ; 115(42): E9916-E9925, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30262654

RESUMO

NMDA-receptor antibodies (NMDAR-Abs) cause an autoimmune encephalitis with a diverse range of EEG abnormalities. NMDAR-Abs are believed to disrupt receptor function, but how blocking this excitatory synaptic receptor can lead to paroxysmal EEG abnormalities-or even seizures-is poorly understood. Here we show that NMDAR-Abs change intrinsic cortical connections and neuronal population dynamics to alter the spectral composition of spontaneous EEG activity and predispose brain dynamics to paroxysmal abnormalities. Based on local field potential recordings in a mouse model, we first validate a dynamic causal model of NMDAR-Ab effects on cortical microcircuitry. Using this model, we then identify the key synaptic parameters that best explain EEG paroxysms in pediatric patients with NMDAR-Ab encephalitis. Finally, we use the mouse model to show that NMDAR-Ab-related changes render microcircuitry critically susceptible to overt EEG paroxysms when these key parameters are changed, even though the same parameter fluctuations are tolerated in the in silico model of the control condition. These findings offer mechanistic insights into circuit-level dysfunction induced by NMDAR-Ab.


Assuntos
Anticorpos/efeitos adversos , Encéfalo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Sincronização Cortical/efeitos dos fármacos , Encefalite/etiologia , Receptores de N-Metil-D-Aspartato/imunologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Córtex Cerebral/imunologia , Córtex Cerebral/metabolismo , Encefalite/metabolismo , Encefalite/patologia , Potenciais Pós-Sinápticos Excitadores , Humanos , Camundongos
7.
Neuroscience ; 388: 118-127, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30031125

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorders. Neuroinflammation plays an important role in the pathogenesis of PD. Long noncoding RNA small nucleolar RNA host gene 1 (SNHG1) was elevated in the brain specimens of PD patients and MPP+-treated SH-SY5Y cells. The expression of mouse Snhg1 and miR-7 was firstly determined in lipopolysaccharide (LPS)-induced BV2 cells. The role and mechanism of SNHG1 in the neuroinflammation of PD were investigated using gain- and loss-of function approaches both in vitro and in vivo. Snhg1 expression was elevated, whereas miR-7 reduced in LPS-induced BV2 cells. Upregulation of Snhg1 elevated, and Snhg1 knockdown suppressed LPS-induced BV2 microglial activation and inflammation. miR-7 reversed, while anti-miR-7 further enhanced the effects of Snhg1 on BV2 cells. Furthermore, we found that Snhg1 functioned as a competing endogenous RNA for miR-7 to regulate nod-like receptor protein 3 (NLRP3) expression, leading to the activation of NLRP3 inflammasome. In the microglial culture supernatant transfer model, knockdown of Snhg1 or NLRP3 in LPS-stimulated BV2 cells inhibited primary neurons from apoptosis and elevated caspase-3 activity. Additionally, Snhg1 was increased in MPTP-induced PD mouse models. Downregulation of Snhg1 elevated miR-7 expression, suppressed the activation of microglia and NLRP3 inflammasome as well as dopaminergic neuron loss in the midbrain substantia nigra pars compacta in MPTP-treated mice. In conclusion, our study suggests that SNHG1 promotes neuroinflammation in the pathogenesis of PD via modulating miR-7/NLRP3 pathway.


Assuntos
Intoxicação por MPTP/imunologia , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Apoptose/fisiologia , Caspase 3/metabolismo , Células Cultivadas , Córtex Cerebral/imunologia , Córtex Cerebral/patologia , Regulação da Expressão Gênica , Inflamassomos/metabolismo , Intoxicação por MPTP/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/imunologia , Microglia/patologia , Neuroimunomodulação/fisiologia , Neurônios/imunologia , Neurônios/patologia
9.
Int J Mol Sci ; 19(3)2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29494550

RESUMO

Microglia are the resident immune cells of the central nervous system (CNS) and participate in physiological and pathological processes. Their unique developmental nature suggests age-dependent structural and functional impairments that might contribute to neurodegenerative diseases. In the present study, we addressed the age-dependent changes in cortical microglia gene expression patterns and the expression of M1- and M2-like activation markers. Iba1 immunohistochemistry, isolation of cortical microglia followed by fluorescence-activated cell sorting and RNA isolation to analyze transcriptional changes in aged cortical microglia was performed. We provide evidence that aging is associated with decreased numbers of cortical microglia and the establishment of a distinct microglia activation profile including upregulation of Ifi204, Lilrb4, Arhgap, Oas1a, Cd244 and Ildr2. Moreover, flow cytometry revealed that aged cortical microglia express increased levels of Cd206 and Cd36. The data presented in the current study indicate that aged mouse cortical microglia adopt a distinct activation profile, which suggests immunosuppressive and immuno-tolerogenic functions.


Assuntos
Córtex Cerebral/citologia , Córtex Cerebral/imunologia , Tolerância Imunológica , Microglia/imunologia , Microglia/metabolismo , Fatores Etários , Envelhecimento/imunologia , Animais , Biomarcadores , Córtex Cerebral/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Transcriptoma
10.
Brain Behav Immun ; 69: 515-531, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29378262

RESUMO

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of unknown aetiology that causes neurological disabilities in young adults. MS displays different clinical patterns, including recurrent episodes with remission periods ("relapsing-remitting MS" (RRMS)), which can progress over several years to a secondary progressive form (SPMS). However, 10% of patients display persistent progression at the onset of disease ("primary progressive MS" (PPMS)). Currently, no specific therapeutic agents are available for the progressive forms, mainly because the underlying pathogenic mechanisms are not clear and because no animal models have been specifically developed for these forms. The development of MS animal models is required to clarify the pathological mechanisms and to test novel therapeutic agents. In the present work, we overexpressed interleukin 1 beta (IL-1ß) in the cortex to develop an animal model reflecting the main pathological hallmarks of MS. The treated animals presented with neuroinflammation, demyelination, glial activation, and neurodegeneration along with cognitive symptoms and MRI images consistent with MS pathology. We also demonstrated the presence of meningeal inflammation close to cortical lesions, with characteristics similar to those described in MS patients. Systemic pro-inflammatory stimulation caused a flare-up of the cortical lesions and behavioural symptoms, including impairment of working memory and the appearance of anxiety-like symptoms. Our work demonstrated induced cortical lesions, reflecting the main histopathological hallmarks and cognitive impairments characterizing the cortical pathology described in MS patients with progressive forms of the disease.


Assuntos
Córtex Cerebral/patologia , Imunidade Inata/fisiologia , Inflamação/patologia , Esclerose Múltipla Crônica Progressiva/patologia , Animais , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/imunologia , Modelos Animais de Doenças , Progressão da Doença , Inflamação/diagnóstico por imagem , Inflamação/imunologia , Imagem por Ressonância Magnética , Masculino , Atividade Motora/fisiologia , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/imunologia , Ratos , Ratos Wistar
11.
Glia ; 66(4): 708-724, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29226424

RESUMO

Brain inflammation is a critical factor involved in neurodegeneration. Recently, the prostaglandin E2 (PGE2 ) downstream members were suggested to modulate neuroinflammatory responses accompanying neurodegenerative diseases. In this study, we investigated the protective effects of prostaglandin E2 receptor 2 (EP2 ) during TLR3 and TLR4-driven inflammatory response using in vitro primary microglia and ex vivo organotypic hippocampal slice cultures (OHSCs). Depletion of microglia from OHSCs differentially affected TLR3 and TLR4 receptor expression. Poly(I:C) induced the production of prostaglandin E2 in OHSCs by increasing cyclooxygenase (COX-2) and microsomal prostaglandin E synthase (mPGES)-1. Besides, stimulation of OHSCs and microglia with Poly(I:C) upregulated EP2 receptor expression. Co-stimulation of OHSCs and microglia with the EP2 agonist butaprost reduced inflammatory mediators induced by LPS and Poly(I:C). In Poly(I:C) challenged OHSCs, butaprost almost restored microglia ramified morphology and reduced Iba1 immunoreactivity. Importantly, microglia depletion prevented the induction of inflammatory mediators following Poly(I:C) or LPS challenge in OHSCs. Activation of EP2 receptor reversed the Poly(I:C)/LPS-induced phosphorylation of the mitogen activated protein kinases (MAPKs) ERK, p38 MAPK and c-Jun N-terminal kinase (JNK) in microglia. Collectively, these data identify an anti-inflammatory function for EP2 signaling in diverse innate immune responses, through a mechanism that involves the mitogen-activated protein kinases pathway.


Assuntos
Hipocampo/imunologia , Inflamação/metabolismo , Microglia/imunologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Alprostadil/análogos & derivados , Alprostadil/farmacologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/imunologia , Córtex Cerebral/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Imunidade Inata/fisiologia , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Poli I-C , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores de Prostaglandina E Subtipo EP2/agonistas , Técnicas de Cultura de Tecidos , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
12.
Artigo em Inglês | MEDLINE | ID: mdl-29203302

RESUMO

The efficiency of interferon beta (IFNß)-based drugs is considerably limited due to their undesirable properties, especially high immunogenicity. In this study, for the first time we investigated the impact of a computationally designed peptide mimetic of IFNß, called MSPEP27, in the animal model of MS. A peptide library was constructed using the Rosetta program based on the predominant IFNAR1-binding site of IFNß. Molecular docking studies were carried out using ClusPro and HADDOCK tools. The GROMACS package was subsequently used for molecular dynamics (MD) simulations. Validation of peptide-receptor interaction was carried out using intrinsic fluorescence measurements. To explore in silico findings further, experimental autoimmune encephalomyelitis (EAE) was induced by subcutaneous immunization of myelin oligodendrocyte glycoprotein (MOG35-55). Mice were then separated into distinct groups and intravenously received 10 or 20mgkg-1 of MSPEP27 or IFNß. The inflammatory mediators were monitored by immunohistochemistry (IL17, CD11b, CD45), quantitative real-time PCR (MMP2, MMP9, TIMP-1) and enzyme-linked immunosorbent assay (IL1ß, TNFα) methods. Among the library of tolerated peptides, MSPEP27, a peptide with favorable physicochemical properties, was chosen for further experiments. This peptide was shown to significantly interact with IFNAR1 in a dose-dependent manner. Like IFNß, MSPEP27 could efficiently bind to IFNAR1 and form a stable peptide-receptor complex during 30ns MD simulations. In vivo analyses revealed that MSPEP27 could lessen inflammation by modulating the levels of inflammatory mediators. According to our results, MSPEP27 peptide could efficiently bind to IFNAR1 and suppress neuroinflammation in vivo. We conclude that MSPEP27 has protective effects against MOG-induced EAE via reduction of immune dysfunction and inflammation.


Assuntos
Encefalomielite Autoimune Experimental/terapia , Fatores Imunológicos/farmacologia , Imunomodulação , Esclerose Múltipla/terapia , Animais , Córtex Cerebral/imunologia , Encefalomielite Autoimune Experimental/imunologia , Expressão Gênica , Humanos , Fatores Imunológicos/uso terapêutico , Interferon beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Esclerose Múltipla/imunologia , Receptor de Interferon alfa e beta/metabolismo
13.
Neurosci Lett ; 668: 169-173, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28235602

RESUMO

Mesial temporal lobe epilepsy is a serious brain disorder in adults that is often preceded by an initial brain insult, such as status epilepticus (SE), that after a latent period leads to recurrent seizures. Post-SE models are widely used for studies on epileptogenic processes. Previous findings of our laboratory suggested that the Neotropical rodents Proechimys exhibit endogenous antiepileptogenic mechanisms in post-SE models. Strong body of research supports that SE triggers a rapid and dramatic upregulation of inflammatory mediators and vascular endothelial growth factor (VEGF). In this work we found that, in the epilepsy-resistant Proechimys, hippocampal and cortical levels of inflammatory cytokines (IL-1ß, IL-6, IL-10, TNF-α) and VEGF remained unchanged 24h after SE, strongly contrasting to the high levels of post-SE changes observed in Wistar rats. Furthermore, substantial differences in the brain baseline levels of these proteins were encountered between animal species studied. Since inflammatory cytokines and VEGF have been recognized as major orchestrators of the epileptogenic process, our results suggest their role in the antiepileptogenic mechanisms previously described in Proechimys.


Assuntos
Córtex Cerebral/imunologia , Citocinas/metabolismo , Epilepsia do Lobo Temporal/imunologia , Inflamação/imunologia , Estado Epiléptico/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/metabolismo , Hipocampo/imunologia , Hipocampo/metabolismo , Inflamação/metabolismo , Masculino , Agonistas Muscarínicos/farmacologia , Pilocarpina/farmacologia , Ratos , Ratos Wistar , Roedores , Estado Epiléptico/metabolismo
14.
Cell Rep ; 21(11): 3220-3233, 2017 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-29241548

RESUMO

Uncontrolled microglial activation may lead to the development of inflammation-induced brain damage. Here, we uncover a ribosome-based mechanism/checkpoint involved in control of the innate immune response and microglial activation. Using an in vivo model system for analysis of the dynamic translational state of microglial ribosomes, with mRNAs as input and newly synthesized peptides as an output, we find a marked dissociation of microglia mRNA and protein networks following innate immune challenge. Highly upregulated and ribosome-associated mRNAs were not translated, resulting in two distinct microglial molecular signatures, a highly specialized pro-inflammatory mRNA signature and an immunomodulatory/homeostatic protein signature. We find that this is due to specific translational suppression of highly expressed mRNAs through a 3' UTR-mediated mechanism involving the RNA-binding protein SRSF3. This discovery suggests avenues for therapeutic modulation of innate immune response in resident microglia.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Biossíntese de Proteínas , RNA Mensageiro/genética , Fatores de Processamento de Serina-Arginina/genética , Animais , Sítios de Ligação , Córtex Cerebral/imunologia , Córtex Cerebral/patologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes/imunologia , Imunidade Inata/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Microglia/imunologia , Microglia/patologia , Ligação Proteica , RNA Mensageiro/imunologia , Ribossomos/genética , Ribossomos/imunologia , Fatores de Processamento de Serina-Arginina/imunologia , Transdução de Sinais , Transcrição Genética
15.
J Immunol ; 199(10): 3547-3558, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28993512

RESUMO

Traumatic and nontraumatic brain injury results from severe disruptions in the cellular microenvironment leading to massive loss of neuronal populations and increased neuroinflammation. The progressive cascade of secondary events, including ischemia, inflammation, excitotoxicity, and free-radical release, contribute to neural tissue damage. NLRX1 is a member of the NLR family of pattern recognition receptors and is a potent negative regulator of several pathways that significantly modulate many of these events. Thus, we hypothesized that NLRX1 limits immune system signaling in the brain following trauma. To evaluate this hypothesis, we used Nlrx1-/- mice in a controlled cortical impact (CCI) injury murine model of traumatic brain injury (TBI). In this article, we show that Nlrx1-/- mice exhibited significantly larger brain lesions and increased motor deficits following CCI injury. Mechanistically, our data indicate that the NF-κB signaling cascade is significantly upregulated in Nlrx1-/- animals. This upregulation is associated with increased microglia and macrophage populations in the cortical lesion. Using a mouse neuroblastoma cell line (N2A), we also found that NLRX1 significantly reduced apoptosis under hypoxic conditions. In human patients, we identify 15 NLRs that are significantly dysregulated, including significant downregulation of NLRX1 in brain injury following aneurysm. We further demonstrate a concurrent increase in NF-κB signaling that is correlated with aneurysm severity in these human subjects. Together, our data extend the function of NLRX1 beyond its currently characterized role in host-pathogen defense and identify this highly novel NLR as a significant modulator of brain injury progression.


Assuntos
Lesões Encefálicas/imunologia , Córtex Cerebral/imunologia , Hipóxia/imunologia , Aneurisma Intracraniano/imunologia , Microglia/imunologia , Proteínas Mitocondriais/metabolismo , Animais , Apoptose , Lesões Encefálicas/genética , Linhagem Celular Tumoral , Microambiente Celular , Córtex Cerebral/patologia , Regulação da Expressão Gênica , Humanos , Hipóxia/genética , Aneurisma Intracraniano/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genética , NF-kappa B/metabolismo , Estudos Retrospectivos , Transdução de Sinais
16.
J Biol Chem ; 292(45): 18699-18712, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-28972143

RESUMO

In the CNS, microglia are activated in response to injury or infection and in neurodegenerative diseases. The endocytic and cell signaling receptor, LDL receptor-related protein-1 (LRP1), is reported to suppress innate immunity in macrophages and oppose microglial activation. The goal of this study was to identify novel mechanisms by which LRP1 may regulate microglial activation. Using primary cultures of microglia isolated from mouse brains, we demonstrated that LRP1 gene silencing increases expression of proinflammatory mediators; however, the observed response was modest. By contrast, the LRP1 ligand, receptor-associated protein (RAP), robustly activated microglia, and its activity was attenuated in LRP1-deficient cells. An important element of the mechanism by which RAP activated microglia was its ability to cause LRP1 shedding from the plasma membrane. This process eliminated cellular LRP1, which is anti-inflammatory, and generated a soluble product, shed LRP1 (sLRP1), which is potently proinflammatory. Purified sLRP1 induced expression of multiple proinflammatory cytokines and the mRNA encoding inducible nitric-oxide synthase in both LRP1-expressing and -deficient microglia. LPS also stimulated LRP1 shedding, as did the heat-shock protein and LRP1 ligand, calreticulin. Other LRP1 ligands, including α2-macroglobulin and tissue-type plasminogen activator, failed to cause LRP1 shedding. Treatment of microglia with a metalloproteinase inhibitor inhibited LRP1 shedding and significantly attenuated RAP-induced cytokine expression. RAP and sLRP1 both caused neuroinflammation in vivo when administered by stereotaxic injection into mouse spinal cords. Collectively, these results suggest that LRP1 shedding from microglia may amplify and sustain neuroinflammation in response to proinflammatory stimuli.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Córtex Cerebral/metabolismo , Mediadores da Inflamação/agonistas , Microglia/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de LDL/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Animais Recém-Nascidos , Calreticulina/genética , Calreticulina/metabolismo , Micropartículas Derivadas de Células/efeitos dos fármacos , Micropartículas Derivadas de Células/imunologia , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo , Ligantes , Lipopolissacarídeos/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Óxido Nítrico Sintase Tipo II/química , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Interferência de RNA , Receptores de LDL/agonistas , Receptores de LDL/antagonistas & inibidores , Receptores de LDL/genética , Proteínas Recombinantes/metabolismo , Proteínas Supressoras de Tumor/agonistas , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética
17.
Nutrients ; 9(10)2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28961195

RESUMO

Choline is involved in relevant neurochemical processes. In particular, it is the precursor and metabolite of acetylcholine (ACh). Choline is an essential component of different membrane phospholipids that are involved in intraneuronal signal transduction. On the other hand, cholinergic precursors are involved in ACh release and carry out a neuroprotective effect based on an anti-inflammatory action. Based on these findings, the present study was designed to evaluate the effects of choline and choline precursor (Choline alphoscerate, GPC) in the modulation of inflammatory processes in the rat brain. Male Wistar rats were intraperitoneally treated with 87 mg of choline chloride/kg/day (65 mg/kg/day of choline), and at choline-equivalent doses of GPC (150 mg/kg/day) and vehicle for two weeks. The brains were dissected and used for immunochemical and immunohistochemical analysis. Inflammatory cytokines (Interleukin-1ß, IL-1ß; Interleukin-6 , IL-6 and Tumor Necrosis Factor-α, TNF-α) and endothelial adhesion molecules (Intercellular Adhesion Molecule, ICAM-1 and Vascular cell Adhesion Molecule, VCAM-1) were studied in the frontal cortex, hippocampus, and cerebellum. The results clearly demonstrated that treatment with choline or GPC did not affect the expression of the inflammatory markers in the different cerebral areas evaluated. Therefore, choline and GPC did not stimulate the inflammatory processes that we assessed in this study.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Córtex Cerebral/efeitos dos fármacos , Colina/uso terapêutico , Encefalite/prevenção & controle , Glicerilfosforilcolina/uso terapêutico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Biomarcadores/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/imunologia , Cerebelo/metabolismo , Cerebelo/patologia , Córtex Cerebral/imunologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Colina/administração & dosagem , Colina/efeitos adversos , Citocinas/metabolismo , Encefalite/imunologia , Encefalite/metabolismo , Encefalite/patologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/imunologia , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Glicerilfosforilcolina/administração & dosagem , Glicerilfosforilcolina/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intraperitoneais , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/líquido cefalorraquidiano , Ratos Wistar , Molécula 1 de Adesão de Célula Vascular/metabolismo
18.
PLoS One ; 12(8): e0183443, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28820892

RESUMO

An association between maternal IgG antibodies reactive against proteins in fetal brain and an outcome of autism in the child has been identified. Using a mouse model of prenatal intraventricular administration of autism-specific maternal IgG, we demonstrated that these antibodies produce behavioral alterations similar to those in children with ASD. We previously demonstrated that these antibodies bind to radial glial stem cells (RG) and observed an increase in the number of divisions of translocating RG in the developing cortex. We also showed an alteration in brain size and as well as a generalized increased of neuronal volume in adult mice. Here, we used our intraventricular mouse model of antibody administration, followed by Golgi and Neurolucida analysis to demonstrate that during midstages of neurogenesis these maternal autism-specific antibodies produced a consistent decrease in the number of spines in the infragranular layers in the adult cortical areas analyzed. Specifically, in the frontal cortex basal dendrites of layer V neurons were decreased in length and volume, and both the total number of spines-mature and immature-and the spine density were lower than in the control neurons from the same region. Further, in the occipital cortex layer VI neurons presented with a decrease in the total number of spines and in the spine density in the apical dendrite, as well as decrease in the number of mature spines in the apical and basal dendrites. Interestingly, the time of exposure to these antibodies (E14.5) coincides with the generation of pyramidal neurons in layer V in the frontal cortex and in layer VI in the occipital cortex, following the normal rostro-caudal pattern of cortical cell generation. We recently demonstrated that one of the primary antigens recognized by these antibodies corresponds to stress-induced phosphoprotein 1 (STIP1). Here we hypothesize that the reduction in the access of newborn cells to STIP1 in the developing cortex may be responsible for the reduced dendritic arborization and number of spines we noted in the adult cortex.


Assuntos
Autoanticorpos/imunologia , Córtex Cerebral/imunologia , Espinhas Dendríticas/imunologia , Animais , Córtex Cerebral/citologia , Feminino , Camundongos , Gravidez
19.
Transl Psychiatry ; 7(8): e1192, 2017 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-28786974

RESUMO

The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in 'high' and 'low' proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances.


Assuntos
Córtex Cerebral/imunologia , Imunoglobulina G/metabolismo , Esquizofrenia/imunologia , Adulto , Animais , Córtex Cerebral/metabolismo , Feminino , Humanos , Imunoglobulina G/sangue , Macaca mulatta , Masculino , Esquizofrenia/metabolismo
20.
Brain Res ; 1673: 72-77, 2017 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-28779977

RESUMO

Alzheimer's disease is a neurodegenerative disease that affects many patients worldwide. The amyloid cascade hypothesis has been adopted by most researchers as the mechanism underlying Alzheimer's disease. Aß plaques have been considered the core factor in the neurotoxic effect in Alzheimer's disease, though some controversy remains. Further effort is necessary to elucidate the mechanism and to develop effective treatments. Previous studies have indicated that eliminating Aß plaques could improve synaptic plasticity and cognitive function. Researchers have developed various forms of vaccines to prevent Aß deposition or eliminate Aß plaques and have made some progress. We developed a new vaccine, Aß3-10-KLH, to increase the level of the anti-Aß immune response, and we show that this vaccine resulted in a sustained prevention of Aß deposition at 4 months after cessation of the vaccine treatment. At the same time point, the expression of synaptophysin and NMDAR2B in APP/PS1 transgenic mice was increased by immunization.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Vacinas contra Alzheimer/imunologia , Peptídeos beta-Amiloides/imunologia , Vacinas/imunologia , Doença de Alzheimer/imunologia , Vacinas contra Alzheimer/administração & dosagem , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Córtex Cerebral/imunologia , Córtex Cerebral/patologia , Modelos Animais de Doenças , Hipocampo/imunologia , Hipocampo/patologia , Humanos , Imuno-Histoquímica , Camundongos Transgênicos , Neuroproteção , Placa Amiloide/imunologia , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Presenilina-1/genética , Presenilina-1/metabolismo , Distribuição Aleatória , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/imunologia , Sinapses/patologia , Sinaptofisina/metabolismo , Vacinação , Vacinas/administração & dosagem
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