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1.
Front Immunol ; 11: 2192, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072084

RESUMO

During the last years probiotics gained the attention of clinicians for their use in the prevention and treatment of multiple diseases. Probiotics main mechanisms of action include enhanced mucosal barrier function, direct antagonism with pathogens, inhibition of bacterial adherence and invasion capacity in the intestinal epithelium, boosting of the immune system and regulation of the central nervous system. It is accepted that there is a mutual communication between the gut microbiota and the liver, the so-called "microbiota-gut-liver axis" as well as a reciprocal communication between the intestinal microbiota and the central nervous system through the "microbiota-gut-brain axis." Moreover, recently the "gut-lung axis" in bacterial and viral infections is considerably discussed for bacterial and viral infections, as the intestinal microbiota amplifies the alveolar macrophage activity having a protective role in the host defense against pneumonia. The importance of the normal human intestinal microbiota is recognized in the preservation of health. Disease states such as, infections, autoimmune conditions, allergy and other may occur when the intestinal balance is disturbed. Probiotics seem to be a promising approach to prevent and even reduce the symptoms of such clinical states as an adjuvant therapy by preserving the balance of the normal intestinal microbiota and improving the immune system. The present review states globally all different disorders in which probiotics can be given. To date, Stronger data in favor of their clinical use are provided in the prevention of gastrointestinal disorders, antibiotic-associated diarrhea, allergy and respiratory infections. We hereby discuss the role of probiotics in the reduction of the respiratory infection symptoms and we focus on the possibility to use them as an adjuvant to the therapeutic approach of the pandemic COVID-19. Nevertheless, it is accepted by the scientific community that more clinical studies should be undertaken in large samples of diseased populations so that the assessment of their therapeutic potential provide us with strong evidence for their efficacy and safety in clinical use.


Assuntos
Bactérias/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus , Microbioma Gastrointestinal/imunologia , Pandemias , Pneumonia Viral , Probióticos/uso terapêutico , Aderência Bacteriana/imunologia , Encéfalo/imunologia , Encéfalo/microbiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/microbiologia , Infecções por Coronavirus/terapia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/microbiologia , Pneumonia Viral/terapia
3.
Nat Commun ; 11(1): 3912, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764562

RESUMO

Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Here, we generate distinct imageable syngeneic mouse GBM-tumor models and utilize RNA-sequencing, CyTOF and correlative immunohistochemistry to assess immune-profiles in these models. We identify immunologically-inert and -active syngeneic-tumor types and show that inert tumors have an immune-suppressive phenotype with numerous exhausted CD8 T cells and resident macrophages; fewer eosinophils and SiglecF+ macrophages. To mimic the clinical-settings of first line of GBM-treatment, we show that tumor-resection invigorates an anti-tumor response via increasing T cells, activated microglia and SiglecF+ macrophages and decreasing resident macrophages. A comparative CyTOF analysis of resected-tumor samples from GBM-patients and mouse GBM-tumors show stark similarities in one of the mouse GBM-tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Tolerância Imunológica , Imunofenotipagem , Imunoterapia , Isoenxertos , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Microambiente Tumoral/imunologia
5.
ACS Chem Neurosci ; 11(15): 2159-2162, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32786343

RESUMO

Immune system and renin-angiotensin-aldosterone system dysregulation with associated cytokine release syndrome may be a key feature of early stage of SARS-CoV-2 organotropism and infection. Following viral mediated brain injury, dysregulated neurochemical activity may cause neurogenic stress cardiomyopathy, which is characterized by transient myocardial dysfunction and arrhythmias. Cardiomyopathy along with acute acute inflammatory thromboembolism and endotheliitis (fragile endothelium) might at least partially explain the underlying mechanisms of rapidly evolving life-threatening COVID-19. Further studies are clearly required to explore these complex pathologies.


Assuntos
Betacoronavirus/metabolismo , Química Encefálica/fisiologia , Encéfalo/metabolismo , Infecções por Coronavirus/metabolismo , Endotélio Vascular/metabolismo , Pneumonia Viral/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/patologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Humanos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Sistema Renina-Angiotensina/fisiologia
6.
Ecotoxicol Environ Saf ; 203: 110993, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32678762

RESUMO

Arsenic (As) and copper (Cu) are common environmental pollutants in nature. When they are excessively present in living organisms, they can cause heavy metal poisoning. There were relatively few studies of the toxicological concentrations of As and Cu in the brain using chicken as a model. Therefore, in this study, arsenic trioxide or/and copper sulfate were added to chicken diets for a 12-week toxicity test. The test results showed that excessive intake of As or/and Cu led to a significant reduction in the total antioxidant capacity (T-AOC), catalase (CAT) and hydroxyl radicals. And significant increase in nitric oxide synthase (NOS) indicates an imbalanced oxidation reaction. In addition, the increase in heat shock protein (HSPs), the increase of NF-κB pathway-related pro-inflammatory mediators, the change of apoptosis factors on the death receptor and mitochondrial apoptosis pathway show that, As or/and Cu exposure induced chicken brain has heat shock response (HSP), tissue inflammation and apoptosis. This damage is inseparable from the oxidative imbalance. It is worth noting that these injury changes are time-dependent, and the combined effect of these two metals is more severe than that of a single group of injuries. Our findings can inform the regulation of animal feed additives and avoid agricultural economic losses or biological health damage.


Assuntos
Apoptose/efeitos dos fármacos , Trióxido de Arsênio/toxicidade , Encéfalo/efeitos dos fármacos , Sulfato de Cobre/toxicidade , Poluentes Ambientais/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Galinhas , Proteínas de Choque Térmico/metabolismo , Inflamação , Masculino , Mitocôndrias/metabolismo , NF-kappa B/metabolismo
7.
Front Immunol ; 11: 1472, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655579

RESUMO

Severe acute respiratory syndrome coronavirus 2 has spread rapidly around the globe. However, despite its high pathogenicity and transmissibility, the severity of the associated disease, COVID-19, varies widely. While the prognosis is favorable in most patients, critical illness, manifested by respiratory distress, thromboembolism, shock, and multi-organ failure, has been reported in about 5% of cases. Several studies have associated poor COVID-19 outcomes with the exhaustion of natural killer cells and cytotoxic T cells, lymphopenia, and elevated serum levels of D-dimer. In this article, we propose a common pathophysiological denominator for these negative prognostic markers, endogenous, angiotensin II toxicity. We hypothesize that, like in avian influenza, the outlook of COVID-19 is negatively correlated with the intracellular accumulation of angiotensin II promoted by the viral blockade of its degrading enzyme receptors. In this model, upregulated angiotensin II causes premature vascular senescence, leading to dysfunctional coagulation, and immunity. We further hypothesize that angiotensin II blockers and immune checkpoint inhibitors may be salutary for COVID-19 patients with critical illness by reversing both the clotting and immune defects (Graphical Abstract).


Assuntos
Angiotensina II/sangue , Betacoronavirus/metabolismo , Infecções por Coronavirus/sangue , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/sangue , Pneumonia Viral/fisiopatologia , Regulação para Cima , Fatores Etários , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Encéfalo/imunologia , Encéfalo/metabolismo , Senescência Celular/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Estado Terminal , Citocinas/metabolismo , Dopamina/metabolismo , Regulação para Baixo , Humanos , Imunoterapia/métodos , Mitocôndrias/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Prognóstico , Sistema Renina-Angiotensina/imunologia
8.
Adv Pharmacol ; 89: 195-235, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616207

RESUMO

As a field, psychiatry is undergoing an exciting paradigm shift toward early identification and intervention that will likely minimize both the burden associated with severe mental illnesses as well as their duration. In this context, the rapid-acting antidepressant ketamine has revolutionized our understanding of antidepressant response and greatly expanded the pharmacologic armamentarium for treatment-resistant depression. Efforts to characterize biomarkers of ketamine response support a growing emphasis on early identification, which would allow clinicians to identify biologically enriched subgroups with treatment-resistant depression who are more likely to benefit from ketamine therapy. This chapter presents a broad overview of a range of translational biomarkers, including those drawn from imaging and electrophysiological studies, sleep and circadian rhythms, and HPA axis/endocrine function as well as metabolic, immune, (epi)genetic, and neurotrophic biomarkers related to ketamine response. Ketamine's unique, rapid-acting properties may serve as a model to explore a whole new class of novel rapid-acting treatments with the potential to revolutionize drug development and discovery. However, it should be noted that although several of the biomarkers reviewed here provide promising insights into ketamine's mechanism of action, most studies have focused on acute rather than longer-term antidepressant effects and, at present, none of the biomarkers are ready for clinical use.


Assuntos
Biomarcadores/metabolismo , Encéfalo/metabolismo , Ketamina/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Ritmo Circadiano/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Ketamina/farmacologia
9.
Mol Immunol ; 125: 70-82, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32652362

RESUMO

Immune responses and central nervous system dysfunction are two main factors to be considered during rabies virus (RABV) infection. However, the mechanisms by which RABV strains of different virulence regulate with chemokine expression and the signaling pathways responsible for the immune responses in the terminal stage of infection both in vivo and in vitro have not been fully elucidated. In this study, we found low expression levels of proinflammatory chemokines in the mouse brain upon infection with street RABV strains (CXZ17 and HN10) at the late stage of infection. We also examined the difference in inflammatory response upon infection with RABV strains of different virulence in a mouse model. We found that the expression of proinflammatory chemokines increased to a varying degree upon infection with street RABV (CXZ17 and HN10) or laboratory-fixed RABV (CVS-11, aG, and CTN); CXCL10, CCL5, and CCL2 were the most significantly upregulated chemokines in brain tissue and microglial BV-2 cells in response to infection with RABV strains of different virulence. Our data also demonstrate significant activation of the MAPK and NF-κB pathways in mouse brain tissue at the late stage of RABV infection. We also found (i) low phosphorylation signals of MAPK and NF-κB p65 in neuronal cells upon infection with CXZ17 and HN10 in the mouse brain and (ii) strong phosphorylation signals in cerebrovascular endothelial cells and neuronal cells upon CTN or aG infection. Moreover, we quantified the nuclear localization status of MAPK signals and NF-κB p65 upon infection with CVS-11, aG, and CTN in BV-2 cells in vitro. We also found (i) that the activation of the p38, ERK1/2, and NF-κB p65 pathway, which stimulates CXCL10, CCL5, and CCL2 expression upon infection with RABV strains of different virulence (aG, CTN, and CVS-11), is triggered after virus entry into BV-2 cells and (ii) that the expression of CXCL10, CCL5, and CCL2 is required for the activation of NF-κB, p38, and ERK1/2, but not JNK. Overall, our study provides insight into the regulation of inflammatory responses mediated by MAPK and NF-κB in the mouse brain and in microglial cells upon RABV infection of different virulence.


Assuntos
Encéfalo/virologia , Inflamação/virologia , Sistema de Sinalização das MAP Quinases/imunologia , NF-kappa B/imunologia , Vírus da Raiva/patogenicidade , Raiva/imunologia , Animais , Encéfalo/imunologia , Inflamação/imunologia , Camundongos , Microglia/imunologia , Microglia/virologia , Vírus da Raiva/imunologia , Virulência/imunologia
10.
Nat Commun ; 11(1): 3687, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703941

RESUMO

Microglia, resident immune cells of the CNS, are thought to defend against infections. Toxoplasma gondii is an opportunistic infection that can cause severe neurological disease. Here we report that during T. gondii infection a strong NF-κB and inflammatory cytokine transcriptional signature is overrepresented in blood-derived macrophages versus microglia. Interestingly, IL-1α is enriched in microglia and IL-1ß in macrophages. We find that mice lacking IL-1R1 or IL-1α, but not IL-1ß, have impaired parasite control and immune cell infiltration within the brain. Further, we show that microglia, not peripheral myeloid cells, release IL-1α ex vivo. Finally, we show that ex vivo IL-1α release is gasdermin-D dependent, and that gasdermin-D and caspase-1/11 deficient mice show deficits in brain inflammation and parasite control. These results demonstrate that microglia and macrophages are differently equipped to propagate inflammation, and that in chronic T. gondii infection, microglia can release the alarmin IL-1α, promoting neuroinflammation and parasite control.


Assuntos
Interleucina-1alfa/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Microglia/imunologia , Proteínas de Ligação a Fosfato/metabolismo , Toxoplasma/imunologia , Toxoplasmose Cerebral/imunologia , Animais , Encéfalo/citologia , Encéfalo/imunologia , Encéfalo/parasitologia , Encéfalo/patologia , Células Cultivadas , Doença Crônica , Modelos Animais de Doenças , Humanos , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Microglia/metabolismo , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/imunologia , Toxoplasma/isolamento & purificação , Toxoplasmose Cerebral/sangue , Toxoplasmose Cerebral/parasitologia , Toxoplasmose Cerebral/patologia
11.
J Vis Exp ; (159)2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32510499

RESUMO

The central nervous system (CNS) is comprised of the brain and spinal cord and is enveloped by the meninges, membranous layers serving as a barrier between the periphery and the CNS. The CNS is an immunologically specialized site, and in steady state conditions, immune privilege is most evident in the CNS parenchyma. In contrast, the meninges harbor a diverse array of resident cells, including innate and adaptive immune cells. During inflammatory conditions triggered by CNS injury, autoimmunity, infection, or even neurodegeneration, peripherally derived immune cells may enter the parenchyma and take up residence within the meninges. These cells are thought to perform both beneficial and detrimental actions during CNS disease pathogenesis. Despite this knowledge, the meninges are often overlooked when analyzing the CNS compartment, because conventional CNS tissue extraction methods omit the meningeal layers. This protocol presents two distinct methods for the rapid isolation of murine CNS tissues (i.e., brain, spinal cord, and meninges) that are suitable for downstream analysis via single-cell techniques, immunohistochemistry, and in situ hybridization methods. The described methods provide a comprehensive analysis of CNS tissues, ideal for assessing the phenotype, function, and localization of cells occupying the CNS compartment under homeostatic conditions and during disease pathogenesis.


Assuntos
Sistema Nervoso Central/citologia , Sistema Nervoso Central/imunologia , Meninges/citologia , Meninges/imunologia , Animais , Encéfalo/citologia , Encéfalo/imunologia , Agregação Celular , Criopreservação , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/virologia , Feminino , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Inclusão em Parafina , Medula Espinal/citologia , Medula Espinal/imunologia , Theilovirus/fisiologia , Fixação de Tecidos
12.
Trends Cogn Sci ; 24(9): 717-733, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32561254

RESUMO

Never before have we experienced social isolation on such a massive scale as we have in response to coronavirus disease 2019 (COVID-19). However, we know that the social environment has a dramatic impact on our sense of life satisfaction and well-being. In times of distress, crisis, or disaster, human resilience depends on the richness and strength of social connections, as well as on active engagement in groups and communities. Over recent years, evidence emerging from various disciplines has made it abundantly clear: perceived social isolation (i.e., loneliness) may be the most potent threat to survival and longevity. We highlight the benefits of social bonds, the choreographies of bond creation and maintenance, as well as the neurocognitive basis of social isolation and its deep consequences for mental and physical health.


Assuntos
Encéfalo/fisiopatologia , Controle de Doenças Transmissíveis , Infecções por Coronavirus/prevenção & controle , Relações Interpessoais , Redes Sociais Online , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Isolamento Social/psicologia , Betacoronavirus , Encéfalo/imunologia , Encéfalo/metabolismo , Demência , Humanos , Solidão/psicologia , Vias Neurais , Resiliência Psicológica , Distância Social , Rede Social , Percepção Social
13.
PLoS One ; 15(6): e0232493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511256

RESUMO

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF`FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/terapia , Peptídeos/farmacologia , Complicações na Gravidez/tratamento farmacológico , Nascimento Prematuro/prevenção & controle , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Encéfalo/imunologia , Linhagem Celular , Modelos Animais de Doenças , Feminino , Inflamação/imunologia , Lipopolissacarídeos , Camundongos , Microglia/efeitos dos fármacos , Microglia/imunologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Gravidez , Complicações na Gravidez/imunologia , Nascimento Prematuro/imunologia
14.
Nat Immunol ; 21(7): 802-815, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541832

RESUMO

Microglia and central nervous system (CNS)-associated macrophages (CAMs), such as perivascular and meningeal macrophages, are implicated in virtually all diseases of the CNS. However, little is known about their cell-type-specific roles in the absence of suitable tools that would allow for functional discrimination between the ontogenetically closely related microglia and CAMs. To develop a new microglia gene targeting model, we first applied massively parallel single-cell analyses to compare microglia and CAM signatures during homeostasis and disease and identified hexosaminidase subunit beta (Hexb) as a stably expressed microglia core gene, whereas other microglia core genes were substantially downregulated during pathologies. Next, we generated HexbtdTomato mice to stably monitor microglia behavior in vivo. Finally, the Hexb locus was employed for tamoxifen-inducible Cre-mediated gene manipulation in microglia and for fate mapping of microglia but not CAMs. In sum, we provide valuable new genetic tools to specifically study microglia functions in the CNS.


Assuntos
Encéfalo/patologia , Encefalomielite Autoimune Experimental/patologia , Traumatismos do Nervo Facial/patologia , Microglia/metabolismo , Cadeia beta da beta-Hexosaminidase/metabolismo , Animais , Encéfalo/citologia , Encéfalo/imunologia , Sistemas CRISPR-Cas/genética , Encefalomielite Autoimune Experimental/imunologia , Traumatismos do Nervo Facial/imunologia , Técnicas de Introdução de Genes , Genes Reporter/genética , Loci Gênicos/genética , Humanos , Microscopia Intravital , Substâncias Luminescentes/química , Proteínas Luminescentes/química , Proteínas Luminescentes/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Microglia/imunologia , Células NIH 3T3 , RNA-Seq , Análise de Célula Única , Transfecção , Cadeia beta da beta-Hexosaminidase/genética
15.
J Vis Exp ; (160)2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32568235

RESUMO

The neuroinflammatory state of the central nervous system (CNS) plays a key role in physiological and pathological conditions. Microglia, the resident immune cells in the brain, and sometimes the infiltrating bone marrow-derived macrophages (BMDMs), regulate the inflammatory profile of their microenvironment in the CNS. It is now accepted that the extracellular vesicle (EV) populations from immune cells act as immune mediators. Thus, their collection and isolation are important to identify their contents but also evaluate their biological effects on recipient cells. The present data highlight chronological requirements for EV isolation from microglia cells or blood macrophages including the ultracentrifugation and size-exclusion chromatography (SEC) steps. A non-targeted proteomic analysis permitted the validation of protein signatures as EV markers and characterized the biologically active EV contents. Microglia-derived EVs were also functionally used on primary culture of neurons to assess their importance as immune mediators in the neurite outgrowth. The results showed that microglia-derived EVs contribute to facilitate the neurite outgrowth in vitro. In parallel, blood macrophage-derived EVs were functionally used as immune mediators in spheroid cultures of C6 glioma cells, the results showing that these EVs control the glioma cell invasion in vitro. This report highlights the possibility to evaluate the EV-mediated immune cell functions but also understand the molecular bases of such a communication. This deciphering could promote the use of natural vesicles and/or the in vitro preparation of therapeutic vesicles in order to mimic immune properties in the microenvironment of CNS pathologies.


Assuntos
Macrófagos/citologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Linhagem Celular Tumoral , Microglia/citologia , Proteômica , Ratos , Microambiente Tumoral
16.
Nat Commun ; 11(1): 2358, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398649

RESUMO

Sphingosine kinase1 (SphK1) is an acetyl-CoA dependent acetyltransferase which acts on cyclooxygenase2 (COX2) in neurons in a model of Alzheimer's disease (AD). However, the mechanism underlying this activity was unexplored. Here we show that N-acetyl sphingosine (N-AS) is first generated by acetyl-CoA and sphingosine through SphK1. N-AS then acetylates serine 565 (S565) of COX2, and the N-AS-acetylated COX2 induces the production of specialized pro-resolving mediators (SPMs). In a mouse model of AD, microglia show a reduction in N-AS generation, leading to decreased acetyl-S565 COX2 and SPM production. Treatment with N-AS increases acetylated COX2 and N-AS-triggered SPMs in microglia of AD mice, leading to resolution of neuroinflammation, an increase in microglial phagocytosis, and improved memory. Taken together, these results identify a role of N-AS in the dysfunction of microglia in AD.


Assuntos
Doença de Alzheimer/imunologia , Anti-Inflamatórios/farmacologia , Encéfalo/imunologia , Microglia/imunologia , Esfingosina/análogos & derivados , Acetilcoenzima A/metabolismo , Acetilação , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Anti-Inflamatórios/uso terapêutico , Encéfalo/patologia , Linhagem Celular , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Mutagênese , Neurônios , Fagocitose/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Presenilina-1/genética , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Serina/metabolismo , Esfingosina/metabolismo
17.
Nat Commun ; 11(1): 2360, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398677

RESUMO

Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD. [11C]PBR28 Positron Emission Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals-with or without trauma exposure. Prefrontal-limbic TSPO availability in the PTSD group was negatively associated with PTSD symptom severity and was significantly lower than in controls. Higher C-reactive protein levels were also associated with lower prefrontal-limbic TSPO availability and PTSD severity. An independent postmortem study found no differential gene expression in 22 PTSD vs. 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup. These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology.


Assuntos
Encéfalo/imunologia , Microglia/imunologia , Transtornos de Estresse Pós-Traumáticos/imunologia , Acetamidas/administração & dosagem , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Masculino , Microglia/patologia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Piridinas/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Receptores de GABA/imunologia , Receptores de GABA/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Fatores Sexuais , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/patologia , Adulto Jovem
18.
Nat Med ; 26(7): 1048-1053, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32451497

RESUMO

Common germline variants of the APOE gene are major risk modifiers of neurodegenerative and atherosclerotic diseases1-3, but their effect on cancer outcome is poorly defined. Here we report that, in a reversal of their effect on Alzheimer's disease, the APOE4 and APOE2 variants confer favorable and poor outcomes in melanoma, respectively. Mice expressing the human APOE4 allele exhibited reduced melanoma progression and metastasis relative to APOE2 mice. APOE4 mice exhibited enhanced anti-tumor immune activation relative to APOE2 mice, and T cell depletion experiments showed that the effect of APOE genotype on melanoma progression was mediated by altered anti-tumor immunity. Consistently, patients with melanoma carrying the APOE4 variant experienced improved survival in comparison to carriers of APOE2. Notably, APOE4 mice also showed improved outcomes under PD1 immune checkpoint blockade relative to APOE2 mice, and patients carrying APOE4 experienced improved anti-PD1 immunotherapy survival after progression on frontline regimens. Finally, enhancing APOE expression via pharmacologic activation of liver X receptors, previously shown to boost anti-tumor immunity4, exhibited therapeutic efficacy in APOE4 mice but not in APOE2 mice. These findings demonstrate that pre-existing hereditary genetics can impact progression and survival outcomes of a future malignancy and warrant prospective investigation of APOE genotype as a biomarker for melanoma outcome and therapeutic response.


Assuntos
Apolipoproteína E2/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Melanoma/genética , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Genótipo , Mutação em Linhagem Germinativa/genética , Mutação em Linhagem Germinativa/imunologia , Humanos , Melanoma/imunologia , Melanoma/patologia , Camundongos , Camundongos Transgênicos/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
19.
J Virol ; 94(14)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32404525

RESUMO

Mouse hepatitis virus (MHV) is a murine betacoronavirus (m-CoV) that causes a wide range of diseases in mice and rats, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the central nervous system (CNS). MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus-induced neural-cell damage leading to demyelination and axonal loss, which are pathological features of multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia, and their interplay are the primary pathophysiological events leading to disruption of the myelin sheath in MS. However, there is emerging evidence supporting gray matter involvement and degeneration in MS. The investigation of T cell function in the pathogenesis of deep gray matter damage is necessary. Here, we employed RSA59 (an isogenic recombinant strain of MHV-A59)-induced experimental neuroinflammation model to compare the disease in CD4-/- mice with that in CD4+/+ mice at days 5, 10, 15, and 30 postinfection (p.i.). Viral titer estimation, nucleocapsid gene amplification, and viral antinucleocapsid staining confirmed enhanced replication of the virions in the absence of functional CD4+ T cells in the brain. Histopathological analyses showed elevated susceptibility of CD4-/- mice to axonal degeneration in the CNS, with augmented progression of acute poliomyelitis and dorsal root ganglionic inflammation rarely observed in CD4+/+ mice. Depletion of CD4+ T cells showed unique pathological bulbar vacuolation in the brain parenchyma of infected mice with persistent CD11b+ microglia/macrophages in the inflamed regions on day 30 p.i. In summary, the current study suggests that CD4+ T cells are critical for controlling acute-stage poliomyelitis (gray matter inflammation), chronic axonal degeneration, and inflammatory demyelination due to loss of protective antiviral host immunity.IMPORTANCE The current trend in CNS disease biology is to attempt to understand the neural-cell-immune interaction to investigate the underlying mechanism of neuroinflammation, rather than focusing on peripheral immune activation. Most studies in MS are targeted toward understanding the involvement of CNS white matter. However, the importance of gray matter damage has become critical in understanding the long-term progressive neurological disorder. Our study highlights the importance of CD4+ T cells in safeguarding neurons against axonal blebbing and poliomyelitis from murine betacoronavirus-induced neuroinflammation. Current knowledge of the mechanisms that lead to gray matter damage in MS is limited, because the most widely used animal model, experimental autoimmune encephalomyelitis (EAE), does not present this aspect of the disease. Our results, therefore, add to the existing limited knowledge in the field. We also show that the microglia, though important for the initiation of neuroinflammation, cannot establish a protective host immune response without the help of CD4+ T cells.


Assuntos
Axônios/imunologia , Axônios/metabolismo , Antígenos CD4/deficiência , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Vírus da Hepatite Murina/fisiologia , Poliomielite/etiologia , Animais , Axônios/patologia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Infecções por Coronavirus/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Gânglios Espinais/imunologia , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Camundongos
20.
Glia ; 68(11): 2345-2360, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32449994

RESUMO

The present study examines functional contributions of microglia in host defense, demyelination, and remyelination following infection of susceptible mice with a neurotropic coronavirus. Treatment with PLX5622, an inhibitor of colony stimulating factor 1 receptor (CSF1R) that efficiently depletes microglia, prior to infection of the central nervous system (CNS) with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality compared with control mice that correlated with impaired control of viral replication. Single cell RNA sequencing (scRNASeq) of CD45+ cells isolated from the CNS revealed that PLX5622 treatment resulted in muted CD4+ T cell activation profile that was associated with decreased expression of transcripts encoding MHC class II and CD86 in macrophages but not dendritic cells. Evaluation of spinal cord demyelination revealed a marked increase in white matter damage in PLX5622-treated mice that corresponded with elevated expression of transcripts encoding disease-associated proteins Osteopontin (Spp1), Apolipoprotein E (Apoe), and Triggering receptor expressed on myeloid cells 2 (Trem2) that were enriched within macrophages. In addition, PLX5622 treatment dampened expression of Cystatin F (Cst7), Insulin growth factor 1 (Igf1), and lipoprotein lipase (Lpl) within macrophage populations which have been implicated in promoting repair of damaged nerve tissue and this was associated with impaired remyelination. Collectively, these findings argue that microglia tailor the CNS microenvironment to enhance control of coronavirus replication as well as dampen the severity of demyelination and influence repair.


Assuntos
Encéfalo/imunologia , Infecções por Coronavirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Microglia/imunologia , Vírus da Hepatite Murina/imunologia , Compostos Orgânicos/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/virologia , Infecções por Coronavirus/induzido quimicamente , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/virologia
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