RESUMO
Maternal immune activation (MIA) during pregnancy has been increasingly recognized as a critical factor in the development of neurodevelopmental disorders, with potential sex-specific impacts that are not yet fully understood. In this study, we utilized a murine model to explore the behavioral and molecular consequences of MIA induced by lipopolysaccharide (LPS) administration on embryonic day 12.5. Our findings indicate that male offspring exposed to LPS exhibited significant increases in anxiety-like and depression-like behaviors, while female offspring did not show comparable changes. Molecular analyses revealed alterations in pro-inflammatory cytokine levels and synaptic gene expression in male offspring, suggesting that these molecular disruptions may underlie the observed behavioral differences. These results emphasize the importance of considering sex as a biological variable in studies of neurodevelopmental disorders and highlight the need for further molecular investigations to understand the mechanisms driving these sex-specific outcomes. Our study contributes to the growing evidence that prenatal immune challenges play a pivotal role in the etiology of neurodevelopmental disorders and underscores the potential for sex-specific preventative approaches of MIA.
Assuntos
Comportamento Animal , Modelos Animais de Doenças , Lipopolissacarídeos , Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Gravidez , Camundongos , Masculino , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Ansiedade/imunologia , Fatores Sexuais , Depressão/imunologia , Caracteres Sexuais , Camundongos Endogâmicos C57BLRESUMO
The first 1000 days of life is a critical period of development in which adverse circumstances can have long-term consequences for the child's health. Maternal immune activation is associated with increased risk of neurodevelopmental disorders in the child. Aberrant immune responses have been reported in individuals with neurodevelopmental disorders. Moreover, lasting effects of maternal immune activation on the offspring's immune system have been reported. Taken together, this indicates that the effect of maternal immune activation is not limited to the central nervous system. Here, we explore the impact of maternal immune activation on the immune system of the offspring. We first describe the development of the immune system and provide an overview of reported alterations in the cytokine profiles, immune cell profiles, immune cell function, and immune induction in pre-clinical models. Additionally, we highlight recent research on the impact of maternal COVID-19 exposure on the neonatal immune system and the potential health consequences for the child. Our review shows that maternal immune activation alters the offspring's immune system under certain conditions, but the reported effects are conflicting and inconsistent. In general, epigenetic modifications are considered the mechanism for fetal programming. The available data was insufficient to identify specific pathways that may contribute to immune programming. As a consequence of the COVID-19 pandemic, more research now focuses on the possible health effects of maternal immune activation on the offspring. Future research addressing the offspring's immune response to maternal immune activation can elucidate specific pathways that contribute to fetal immune programming and the long-term health effects for the offspring.
Assuntos
COVID-19 , Desenvolvimento Fetal , Sistema Imunitário , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Feminino , Efeitos Tardios da Exposição Pré-Natal/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Desenvolvimento Fetal/imunologia , COVID-19/imunologia , Animais , SARS-CoV-2/imunologia , Epigênese Genética , Citocinas/metabolismo , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/etiologia , Exposição Materna/efeitos adversos , Recém-NascidoRESUMO
Activation of the maternal immune system during gestation has been associated with an increased risk for neurodevelopmental disorders in the offspring, particularly schizophrenia and autism spectrum disorder. Microglia, the tissue-resident macrophages of the central nervous system, are implicated as potential mediators of this increased risk. Early in development, microglia start populating the embryonic central nervous system and in addition to their traditional role as immune responders under homeostatic conditions, microglia are also intricately involved in various early neurodevelopmental processes. The timing of immune activation may interfere with microglia functioning during early neurodevelopment, potentially leading to long-term consequences in postnatal life. In this review we will discuss the involvement of microglia in brain development during the prenatal and early postnatal stages of life, while also examining the effects of maternal immune activation on microglia and neurodevelopmental processes. Additionally, we discuss recent single cell RNA-sequencing studies focusing on microglia during prenatal development, and hypothesize how early life microglial priming, potentially through epigenetic reprogramming, may be related to neurodevelopmental disorders.
Assuntos
Microglia , Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Microglia/imunologia , Microglia/metabolismo , Humanos , Gravidez , Animais , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Feminino , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/embriologia , Epigênese Genética , Suscetibilidade a DoençasRESUMO
The global public health emergency of COVID-19 in January 2020 prompted a surge in research focusing on the pathogenesis and clinical manifestations of the virus. While numerous reports have been published on the acute effects of COVID-19 infection, the review explores the multifaceted long-term implications of COVID-19, with a particular focus on severe maternal COVID-19 infection, gut microbiome dysbiosis, and neurodevelopmental disorders in offspring. Severe COVID-19 infection has been associated with heightened immune system activation and gastrointestinal symptoms. Severe COVID-19 may also result in gut microbiome dysbiosis and a compromised intestinal mucosal barrier, often referred to as 'leaky gut'. Increased gut permeability facilitates the passage of inflammatory cytokines, originating from the inflamed intestinal mucosa and gut, into the bloodstream, thereby influencing fetal development during pregnancy and potentially elevating the risk of neurodevelopmental disorders such as autism and schizophrenia. The current review discusses the role of cytokine signaling molecules, microglia, and synaptic pruning, highlighting their potential involvement in the pathogenesis of neurodevelopmental disorders following maternal COVID-19 infection. Additionally, this review addresses the potential of probiotic interventions to mitigate gut dysbiosis and inflammatory responses associated with COVID-19, offering avenues for future research in optimizing maternal and fetal health outcomes.
Assuntos
COVID-19 , Disbiose , Microbioma Gastrointestinal , Transtornos do Neurodesenvolvimento , Complicações Infecciosas na Gravidez , SARS-CoV-2 , Humanos , COVID-19/imunologia , Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Gravidez , Feminino , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/microbiologia , Complicações Infecciosas na Gravidez/virologia , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/microbiologia , Probióticos/uso terapêutico , Probióticos/administração & dosagem , Citocinas/metabolismo , Citocinas/imunologiaAssuntos
Inflamação , Pré-Eclâmpsia , Humanos , Pré-Eclâmpsia/imunologia , Pré-Eclâmpsia/etiologia , Gravidez , Feminino , Inflamação/imunologia , Inflamação/metabolismo , Desenvolvimento Fetal/imunologia , Animais , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/etiologiaRESUMO
Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools in preclinical research of immune-mediated neurodevelopmental disorders and mental illnesses. Using a viral-like MIA model that is based on prenatal poly(I:C) exposure in mice, we have recently identified the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network and inflammatory profiles even under conditions of genetic homogeneity and identical MIA. Here, we tested the hypothesis that the intrauterine positions of fetuses, which are known to shape individual variability in litter-bearing mammals through variations in fetal hormone exposure, may contribute to the variable outcomes of MIA in mice. MIA was induced by maternal administration of poly(I:C) on gestation day 12 in C57BL/6N mice. Determining intrauterine positions using delivery by Cesarean section (C-section), we found that MIA-exposed offspring developing between female fetuses only (0M-MIA offspring) displayed significant deficits in sociability and sensorimotor gating at adult age, whereas MIA-exposed offspring developing between one or two males in utero (1/2M-MIA offspring) did not show the same deficits. These intrauterine position effects similarly emerged in male and female offspring. Furthermore, while MIA elevated fetal brain levels of pro- and anti-inflammatory cytokines independently of the precise intrauterine position and sex of adjacent fetuses during the acute phase, fetal brain levels of TNF-α remained elevated in 0M-MIA but not 1/2M-MIA offspring until the post-acute phase in late gestation. As expected, 1/2M offspring generally showed higher testosterone levels in the fetal brain during late gestation as compared to 0M offspring, confirming the transfer of testosterone from male fetuses to adjacent male or female fetuses. Taken together, our findings identify a novel source of within-litter variability contributing to heterogeneous outcomes of short- and long-term effects in a mouse model of MIA. In broader context, our findings highlight that individual differences in fetal exposure to hormonal and inflammatory signals may be a perinatal factor that shapes risk and resilience to MIA.
Assuntos
Encéfalo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Poli I-C , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Gravidez , Camundongos , Masculino , Poli I-C/farmacologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Encéfalo/metabolismo , Encéfalo/imunologia , Citocinas/metabolismo , Transtornos do Neurodesenvolvimento/imunologia , Comportamento Animal/fisiologia , Feto/imunologia , Feto/metabolismo , Útero/metabolismo , Útero/imunologiaRESUMO
Maternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.
Assuntos
Encéfalo , Citocinas , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento , Placenta , Efeitos Tardios da Exposição Pré-Natal , Caracteres Sexuais , Feminino , Animais , Gravidez , Masculino , Citocinas/metabolismo , Citocinas/genética , Camundongos , Encéfalo/metabolismo , Encéfalo/imunologia , Encéfalo/embriologia , Placenta/metabolismo , Placenta/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/metabolismo , Poli I-C/toxicidade , Transcriptoma , Modelos Animais de Doenças , Feto/metabolismoRESUMO
About 3-7% of the worldwide population is diagnosed with a neurodevelopmental condition, including autism and attention-deficit hyperactivity disorder. Nonetheless, the aetiology of these conditions is unclear and support options are limited or not effective for all those diagnosed. Cumulating evidence, however, supports a role of the immune system in neurodevelopment, and immune dysregulations have been implicated in neurodevelopmental atypicalities. This knowledge offers tremendous opportunities, especially the possibility to adopt immunomodulatory compounds, which are already available and safe to use, for the management of neurodevelopmental difficulties. This perspective discusses the potential of immune-based interventions in neurodevelopmental care. Here, the application of existing immunomodulatory compounds to symptom management is justified by findings of immune dysregulations across neurodevelopmental conditions and preliminary, encouraging immune-based clinical trials. Still, key considerations are presented, specifically the necessity of immune biomarkers to ensure the right support option for the right (subgroup of) individuals within the neurodevelopmental spectrum.
Assuntos
Transtornos do Neurodesenvolvimento , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/imunologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Sistema Imunitário/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Agentes de Imunomodulação/uso terapêutico , Transtornos do Neurodesenvolvimento/imunologiaRESUMO
Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.
Assuntos
Proteína BRCA1/genética , Mutação em Linhagem Germinativa , Mutação com Perda de Função , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Adolescente , Proteína BRCA1/imunologia , Criança , Pré-Escolar , Cromatina/química , Cromatina/imunologia , Montagem e Desmontagem da Cromatina/genética , Montagem e Desmontagem da Cromatina/imunologia , Família , Feminino , Regulação da Expressão Gênica , Heterozigoto , Histonas/genética , Histonas/imunologia , Fator C1 de Célula Hospedeira/genética , Fator C1 de Célula Hospedeira/imunologia , Humanos , Lactente , Masculino , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/patologia , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/imunologia , Ubiquitina/genética , Ubiquitina/imunologia , Ubiquitina Tiolesterase/deficiência , Ubiquitina Tiolesterase/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , UbiquitinaçãoRESUMO
Maternal immune activation (MIA) with poly(I:C) is a preclinical paradigm for schizophrenia and autism research. Methodological variations, including poly(I:C) molecular weight, contribute to inconsistencies in behavioural and molecular outcomes. We established in Wistar rats that 4 mg/kg high molecular weight (HMW)-poly(I:C) on GD19 induces maternal sickness, smaller litters and maternal elevations of serum cytokines, including increases in monocyte chemoattractants. In adult offspring, we found that males have higher serum cytokines than females, and MIA did not alter peripheral cytokines in either sex. Our study will contribute to the effective use of the MIA model to elucidate the neurobiology of neurodevelopmental disorders.
Assuntos
Proteínas Quimioatraentes de Monócitos/imunologia , Transtornos do Neurodesenvolvimento/imunologia , Poli I-C/toxicidade , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Citocinas/sangue , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Masculino , Poli I-C/imunologia , Gravidez , Ratos , Ratos WistarRESUMO
Mice homozygous for the nude mutation (Foxn1nu) are hairless and exhibit congenital dysgenesis of the thymic epithelium, resulting in a primary immunodeficiency of mature T-cells, and have been used for decades in research with tumour grafts. Early studies have already demonstrated social behaviour impairments and central nervous system (CNS) alterations in these animals, but did not address the complex interplay between CNS, immune system and behavioural alterations. Here we investigate the impact of T-cell immunodeficiency on behaviours relevant to the study of neurodevelopmental and neuropsychiatric disorders. Moreover, we aimed to characterise in a multidisciplinary manner the alterations related to those findings, through evaluation of the excitatory/inhibitory synaptic proteins, cytokines expression and biological spectrum signature of different biomolecules in nude mice CNS. We demonstrate that BALB/c nude mice display sociability impairments, a complex pattern of repetitive behaviours and higher sensitivity to thermal nociception. These animals also have a reduced IFN-γ gene expression in the prefrontal cortex and an absence of T-cells in meningeal tissue, both known modulators of social behaviour. Furthermore, excitatory synaptic protein PSD-95 immunoreactivity was also reduced in the prefrontal cortex, suggesting an intricate involvement of social behaviour related mechanisms. Lastly, employing biospectroscopy analysis, we have demonstrated that BALB/c nude mice have a different CNS spectrochemical signature compared to their heterozygous littermates. Altogether, our results show a comprehensive behavioural analysis of BALB/c nude mice and potential neuroimmunological influences involved with the observed alterations.
Assuntos
Transtornos Mentais/imunologia , Mutação/genética , Transtornos do Neurodesenvolvimento/imunologia , Linfócitos T/imunologia , Animais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4+ T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders.
Assuntos
Transtorno do Espectro Autista/imunologia , Linfócitos T CD4-Positivos/imunologia , Cromatina/metabolismo , Microbioma Gastrointestinal/imunologia , Inflamação/imunologia , Interleucina-17/metabolismo , Intestinos/imunologia , Transtornos do Neurodesenvolvimento/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Transtorno do Espectro Autista/microbiologia , Criança , Modelos Animais de Doenças , Transplante de Microbiota Fecal , Feminino , Humanos , Imunização , Inflamação/microbiologia , Camundongos , Transtornos do Neurodesenvolvimento/microbiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/microbiologiaRESUMO
A strong association between perinatal viral infections and neurodevelopmental disorders has been established. Both the direct contact of the virus with the developing brain and the strong maternal immune response originated by viral infections can impair proper neurodevelopment. Coronavirus disease 2019 (COVID-19), caused by the highly-infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a large global outbreak and is a major public health issue. While initial studies focused on the viral impact on the respiratory system, increasing evidence suggest that SARS-CoV-2 infects other organs and tissues including the mature brain. While studies continue to determine the neuropathology associated to COVID-19, the consequences of SARS-CoV-2 infection to the developing brain remain largely unexplored. The present review discusses evidence suggesting that SARS-CoV-2 infection may have persistent effects on the course of pregnancy and on brain development. Studies have shown that several proinflammatory mediators which are increased in the SARS-CoV-2-associated cytokine storm, are also modified in other viral infections known to increase the risk of neurodevelopmental disorders. In this sense, further studies should assess the genuine effects of SARS-CoV-2 infection during pregnancy and delivery along with an extended follow-up of the offspring, including neurocognitive, neuroimaging, and electrophysiological examination. It also remains to be determined whether and by which mechanisms SARS-CoV-2 intrauterine and early life infection could lead to an increased risk of developing neuropsychiatric disorders, such as autism (ASD) and schizophrenia (SZ), in the offspring.
Assuntos
Transtorno do Espectro Autista/epidemiologia , COVID-19/epidemiologia , Síndrome da Liberação de Citocina/epidemiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Esquizofrenia/epidemiologia , Transtorno do Espectro Autista/imunologia , Encéfalo/embriologia , Encéfalo/imunologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Feminino , Humanos , Transmissão Vertical de Doenças Infecciosas , Transtornos do Neurodesenvolvimento/imunologia , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Fatores de Risco , SARS-CoV-2 , Esquizofrenia/imunologiaRESUMO
Almost 60 years have passed since the initial discovery by Hubel and Wiesel that changes in neuronal activity can elicit developmental rewiring of the central nervous system (CNS). Over this period, we have gained a more comprehensive picture of how both spontaneous neural activity and sensory experience-induced changes in neuronal activity guide CNS circuit development. Here we review activity-dependent synaptic pruning in the mammalian CNS, which we define as the removal of a subset of synapses, while others are maintained, in response to changes in neural activity in the developing nervous system. We discuss the mounting evidence that immune and cell-death molecules are important mechanistic links by which changes in neural activity guide the pruning of specific synapses, emphasizing the role of glial cells in this process. Finally, we discuss how these developmental pruning programmes may go awry in neurodevelopmental disorders of the human CNS, focusing on autism spectrum disorder and schizophrenia. Together, our aim is to give an overview of how the field of activity-dependent pruning research has evolved, led to exciting new questions and guided the identification of new, therapeutically relevant mechanisms that result in aberrant circuit development in neurodevelopmental disorders.
Assuntos
Transtorno do Espectro Autista/fisiopatologia , Sistema Nervoso Central/fisiologia , Imunidade Celular/fisiologia , Plasticidade Neuronal/fisiologia , Esquizofrenia/fisiopatologia , Fatores Etários , Animais , Transtorno do Espectro Autista/imunologia , Sistema Nervoso Central/citologia , Humanos , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Esquizofrenia/imunologiaRESUMO
Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring. The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs). Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring. In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene-environment interface during NDD pathogenesis. For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways. In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome. We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic 'priming' of offspring microglia and postnatal immune-brain crosstalk. The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms.
Assuntos
Interação Gene-Ambiente , Transtornos do Neurodesenvolvimento/imunologia , Neuroimunomodulação/imunologia , Doenças Neuroinflamatórias/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Feminino , Humanos , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , Doenças Neuroinflamatórias/epidemiologia , Doenças Neuroinflamatórias/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genéticaRESUMO
BACKGROUND: Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model. METHODS: On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue. RESULTS: MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen). CONCLUSIONS: MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Encefalopatias Metabólicas/tratamento farmacológico , Minociclina/farmacologia , Malformações do Sistema Nervoso/patologia , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Inibição Pré-Pulso/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Encefalopatias Metabólicas/etiologia , Modelos Animais de Doenças , Feminino , Imageamento por Ressonância Magnética , Masculino , Minociclina/administração & dosagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/etiologia , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/imunologia , Tomografia por Emissão de Pósitrons , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/imunologia , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente , Esquizofrenia/imunologiaRESUMO
The dynamic population of microbes that reside in the gastrointestinal tract plays a pivotal role in orchestrating several aspects of host physiology and health, including but not limited to nutrient extraction and metabolism, as well as the regulation of intestinal epithelial barrier integrity. Gut microbes interact with the host in a bi-directional manner as the microbiota can support the development and education of the innate and adaptive immune systems, thereby conferring protection against pathogens and harmful stimuli while training the host to maintain a homeostatic tolerance towards commensal symbiotics. Recent advances in the field have highlighted the importance of the host-microbiota relationship in neurodevelopment and behaviour, with relevant implications for the onset and progression of brain disorders of inflammatory origin. Microbial modulation of brain function is achieved throughout complex neuro-immune-endocrine pathways of the microbiome-gut-brain axis. Changes in the composition of the gut microbiota or perturbation in microbial-derived metabolites and neuroactive compounds are sensed by the afferent branches of the sympathetic and vagal innervation and transmitted to the central nervous system, which in turn produces behavioural responses. Here, we focus on how the crosstalk between the gut microbiota and the immune system modulates the development and function of the peripheral and central nervous systems. Specific attention is afforded to the involvement of host-microbe neuroimmune interactions in the pathogenesis of neuro-psychiatric and neuroinflammatory disorders such as autism spectrum disorders, anxiety, and depression, as well as Parkinson's and Alzheimer's diseases.
Assuntos
Encéfalo , Microbioma Gastrointestinal/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Fenômenos Fisiológicos do Sistema Nervoso/imunologia , Encéfalo/imunologia , Encéfalo/microbiologia , Humanos , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/psicologia , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/psicologia , NeuroimunomodulaçãoRESUMO
COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) betacoronavirus, affects children in a different way than it does in adults, with milder symptoms. However, several cases of neurological symptoms with neuroinflammatory syndromes, such as the multisystem inflammatory syndrome (MIS-C), following mild cases, have been reported. As with other viral infections, such as rubella, influenza, and cytomegalovirus, SARS-CoV-2 induces a surge of proinflammatory cytokines that affect microglial function, which can be harmful to brain development. Along with the viral induction of neuroinflammation, other noninfectious conditions may interact to produce additional inflammation, such as the nutritional imbalance of fatty acids and polyunsaturated fatty acids and alcohol consumption during pregnancy. Additionally, transient thyrotoxicosis induced by SARS-CoV-2 with secondary autoimmune hypothyroidism has been reported, which could go undetected during pregnancy. Together, those factors may pose additional risk factors for SARS-CoV-2 infection impacting mechanisms of neural development such as synaptic pruning and neural circuitry formation. The present review discusses those conditions in the perspective of the understanding of risk factors that should be considered and the possible emergence of neurodevelopmental disorders in COVID-19-infected children.
Assuntos
Encéfalo/crescimento & desenvolvimento , COVID-19/imunologia , Inflamação/imunologia , Microglia/imunologia , Transtornos do Neurodesenvolvimento/imunologia , Encéfalo/imunologia , Encéfalo/fisiopatologia , COVID-19/fisiopatologia , Dieta , Gorduras Insaturadas na Dieta , Ácidos Graxos Insaturados , Transtornos do Espectro Alcoólico Fetal/imunologia , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Humanos , Inflamação/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Plasticidade Neuronal , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória SistêmicaRESUMO
The immune and nervous systems have unique developmental trajectories that individually build intricate networks of cells with highly specialized functions. These two systems have extensive mechanistic overlap and frequently coordinate to accomplish the proper growth and maturation of an organism. Brain resident innate immune cells - microglia - have the capacity to sculpt neural circuitry and coordinate copious and diverse neurodevelopmental processes. Moreover, many immune cells and immune-related signalling molecules are found in the developing nervous system and contribute to healthy neurodevelopment. In particular, many components of the innate immune system, including Toll-like receptors, cytokines, inflammasomes and phagocytic signals, are critical contributors to healthy brain development. Accordingly, dysfunction in innate immune signalling pathways has been functionally linked to many neurodevelopmental disorders, including autism and schizophrenia. This review discusses the essential roles of microglia and innate immune signalling in the assembly and maintenance of a properly functioning nervous system.