ABSTRACT
Interleukin-17 (IL-17) plays an important role in the body′s immune response and inflammatory response.High levels of IL-17 are associated with a variety of autoimmune diseases, acute and chronic neurodegenerative diseases, and psychiatric disorders.Autism spectrum disorder (ASD) is a group of common neurodevelopmental disorders in childhood.Recent clinical and experimental studies have linked maternal immune activation (MIA) during pregnancy to the risk of ASD in offspring.Significantly increased IL-17 level is found in MIA-induced progeny ASD, which is the key factor leading to neurodevelopmental abnormalities in progeny mice.This article reviews the latest research progress on the relationship between IL-17 and progeny ASD, and provides new ideas for the prevention and treatment of ASD.
ABSTRACT
Resumen: En los últimos años se ha intentado comprender la etiología del Trastorno del Espectro Autista (TEA), evidenciandose que existe una compleja interacción entre factores genéticos y ambientales. Estudios epidemiológicos y en modelos animales sugieren que la activación inmune de la madre durante el embarazo puede asociarse un mayor riesgo de desarrollar TEA en los hijos, destacando el rol de las citoquinas proinflamatorias, los auto-anticuerpos y el rol de la microglia activada en la poda sináptica durante el desarrollo embrionario. Comprender mejor los factores asociados con los Trastornos del Neurodesarrollo permitirá en el futuro desarrollar estrategias de manejo y detección precoz en población de riesgo.
Abstract: Autism Spectrum Disorder (ASD) etiology has been related whit complex interaction between ge netic and environmental factors. In the last years, numerous studies have suggested that maternal immune activation during pregnancy could be related to ASD in the offspring. This relation could be explained by the effects of pro-inflammatory cytokines, autoantibodies and microglial synap tic pruning during early embryonic development. Better understanding of Neurodevelopmental Disorders risk factors will support appropriate strategies of screening and management of risk population.
Subject(s)
Humans , Female , Pregnancy , Pregnancy Complications/immunology , Prenatal Exposure Delayed Effects/immunology , Autism Spectrum Disorder/immunology , Autoantibodies/immunology , Risk Factors , Cytokines/immunology , Microglia/immunology , Autism Spectrum Disorder/etiologyABSTRACT
Autism spectrum disorder is a rapidly increasing heterogeneous neurodevelopmental syndrome, remarked by persistent deficit in social communication, and restricted, repetitive patterns of behavior and interest. Lately, maternal immune activation and micgroglial dysfunction in the developing brain have been gaining mounting evidence and leading to studies of various novel agents as potential treatment options. A few immunomodulatory treatment options—luteolin, minocycline, suramin, vitamin D, gut microbiota—are discussed in the current article, regarding the current understanding of their mechanisms and evidence for potential clinical use. More studies are warranted to understand their exact mechanisms of action and to verify efficacy and safety in human subjects.
Subject(s)
Humans , Autism Spectrum Disorder , Autistic Disorder , Brain , Immunomodulation , Microglia , Minocycline , Suramin , Vitamin DABSTRACT
Increasing evidence has revealed that maternal cytomegalovirus (CMV) infection may be associated with neurodevelopmental disorders in offspring.Potential relevance between the placental inflammation and CMV-related autism has been reported by clinical observation.Meanwhile,abnormal expression of Toll-like receptor 2 (TLR2) and TLR4 in placenta of patients with chorioamnionitis was observed in multiple studies.IL-6 and IL-10 are two important maternal inflammatory mediators involved in neurodevelopmental disorders.To investigate whether murine CMV (MCMV) infection causes alterations in placental IL-6/10 and TLR2/4 levels,we analyzed the dynamic changes in gene expression of TLR2/4 and IL-6/10 in placentas following acute MCMV infection.Mouse model of acute MCMV infection during pregnancy was created,and pre-pregnant MCMV infected,lipopolysaccharide (LPS)-treated and uninfected mice were used as controls.At E13.5,E14.5 and E18.5,placentas and fetal brains were harvested and mRNA expression levels of placental TLR2/4 and IL-6/10 were analyzed.The results showed that after acute MCMV infection,the expression levels of placental TLR2/4 and IL-6 were elevated at E13.5,accompanied by obvious placental inflammation and reduction of placenta and fetal brain weights.However,LPS 50 μg/kg could decrease the IL-6 expression at E13.5 and E14.5.This suggests that acute MCMV infection during pregnancy could up-regulate the gene expression of TLR2/4 in placental trophoblasts and activate them to produce more proinflammatory cytokine IL-6.High dose of LPS stimulation (50 tg/kg) during pregnancy can lead to down-regulation of IL-6 levels in the late stage.Imbalance ofIL-6 expression in placenta might be associated with the neurodevelopmental disorders in progeny.
ABSTRACT
Increasing evidence has revealed that maternal cytomegalovirus (CMV) infection may be associated with neurodevelopmental disorders in offspring.Potential relevance between the placental inflammation and CMV-related autism has been reported by clinical observation.Meanwhile,abnormal expression of Toll-like receptor 2 (TLR2) and TLR4 in placenta of patients with chorioamnionitis was observed in multiple studies.IL-6 and IL-10 are two important maternal inflammatory mediators involved in neurodevelopmental disorders.To investigate whether murine CMV (MCMV) infection causes alterations in placental IL-6/10 and TLR2/4 levels,we analyzed the dynamic changes in gene expression of TLR2/4 and IL-6/10 in placentas following acute MCMV infection.Mouse model of acute MCMV infection during pregnancy was created,and pre-pregnant MCMV infected,lipopolysaccharide (LPS)-treated and uninfected mice were used as controls.At E13.5,E14.5 and E18.5,placentas and fetal brains were harvested and mRNA expression levels of placental TLR2/4 and IL-6/10 were analyzed.The results showed that after acute MCMV infection,the expression levels of placental TLR2/4 and IL-6 were elevated at E13.5,accompanied by obvious placental inflammation and reduction of placenta and fetal brain weights.However,LPS 50 μg/kg could decrease the IL-6 expression at E13.5 and E14.5.This suggests that acute MCMV infection during pregnancy could up-regulate the gene expression of TLR2/4 in placental trophoblasts and activate them to produce more proinflammatory cytokine IL-6.High dose of LPS stimulation (50 tg/kg) during pregnancy can lead to down-regulation of IL-6 levels in the late stage.Imbalance ofIL-6 expression in placenta might be associated with the neurodevelopmental disorders in progeny.
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OBJECTIVE: Prenatal infection is implicated in the etiology of schizophrenia. The objective of this paper is to study the role of complement protein C1q in the psychosis of adult offspring after maternal immune activation (MIA). In addition, effect of 7,8-dihydroxyflavone (7,8-DHF: a tropomyosin receptor kinase B [TrkB] agonist) was also examined. METHODS: Western blot analysis of C1q in the brain regions from adult offspring after prenatal poly(I:C) (5.0 mg/kg/day from E12 to E17) exposure was performed. 7,8-DHF or vehicle was given from 4 to 8-weeks old. RESULTS: Expression of C1q in the prefrontal cortex (PFC) of adult offspring from poly(I:C)-treated pregnant mice was significantly higher than that of control group. Early treatment with 7,8-DHF during juvenile and adolescent stages could prevent an increase of C1q in the PFC of adult offspring after MIA. CONCLUSION: Therefore, it is likely that increased C1q expression in the frontal cortex may play a role in the behavioral abnormalities of adult offspring after MIA. Furthermore, supplementation with a TrkB agonist such as 7,8-DHF during the prodromal stage may have prophylactic effects on the behavioral abnormalities after MIA.
Subject(s)
Adolescent , Adult , Animals , Humans , Mice , Adult Children , Blotting, Western , Brain , Brain-Derived Neurotrophic Factor , Complement System Proteins , Frontal Lobe , Phosphotransferases , Prefrontal Cortex , Prodromal Symptoms , Psychotic Disorders , Schizophrenia , TropomyosinABSTRACT
Objective To investigate if the positive postnatal environment could modify the schizo-phrenia-related behaviors caused by early maternal immune activation,and the interaction of this two pre-and postnatal factors.Methods The pregnant mice were randomly divided into experimental and control groups.The experimental groups were injected with polynosinic-polycytidylic acid(Poly I : C)(5mg/kg),via intra-venous route,at gestational day 9.The control groups were injected with the same volume of normal saline (NS)at the same gestational day.All offspring were housed in groups of littermates until postnatal day (PND)21 when they were weaned.Between PND22-PND60,offspring were divided into dull or enriched en-vironment(DE or EE)groups by sex and treatment.Different toys were put into the cages of enriched envi-ronment group every week,such as running wheels,climbing materials,swings and rollers.The dull environ-ment(DE)groups were kept the normal housing environment only with sawdust.At PND60,behavioral tests were conducted,such as prepulse inhibition(PPI),open field test,novel object/location recognition,social interaction test,as well as water maze test,were conducted to evaluate the performance of all offspring.After behavioral tests,all offspring were killed and the hippocampus were dissected.The western blot was used to analyze the expression of myelin basic protein in the hippocampus.Results (1)The percentage of PPI with early maternal immune activation of Poly I : C were significantly reduced when compared with control groups (female offspring:F=28.12,P<0.001;male offspring:F=14.76,P<0.01),suggesting the schizophrenia-like behavioral deficit in the offspring induced by early prenatal Poly I : C challenge.(2)In open field test,early maternal immune activation increased the moved distance and speed of the offspring compared with the con-trol groups(female offspring:distances,F=5.10,P<0.05,speed:F=5.19,P<0.05;male offspring:distances:F=6.76,P<0.05,velocity:F=6.85,P<0.05,vs each corresponding control).(3)Enriched environment in-creased the social interaction time of offspring with strange mouse in the social interaction test(female off-spring:EE group(101.30±6.83)s,DE group(76.50±5.59)s,F=9.41,P<0.01;male offspring:EE group(98. 52±6.82)s,DE group(75.82±3.95)s,F=7.95,P<0.01).(4)Enriched environment decreased the time for offspring to find the platform in water maze test(P<0.05).(5)The expression of myelin basic protein in hip-pocampus in offspring which received early maternal immune activation by Poly I : C was lower than that in the control groups(P<0.05).Conclusion The postnatal enriched environment increased the social interac-tion and the learning abilities of the offspring with early maternal immune activation by Poly I : C in water maze,and even more improved the perseveration behavior of the offspring induced by the early maternal im-mune activation.
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Substantial evidence suggests a direct link between periodontitis in pregnant women and subsequent adverse pregnancy outcomes. However, no studies have evaluated the transgenerational effects of periodontitis on the reproductive performance of subsequent generations. The present study investigated whether maternal periodontal disease exerts deleterious transgenerational effects on reproductive performance in F1 female rats. Rat female offspring from mothers that were subjected to experimentally induced periodontitis or sham operation were mated with sexually experienced male rats. The weight and reproductive performance of these F1 offspring were evaluated on gestation day 21, including maternal weight, litter weight, individual pup weight, number of pups, and number of resorptions. The percentage of dams with resorptions and the litter weight/number of pups were also calculated. Compared with the control group, an increase was observed in the percentage and number of resorptions and litter weight/number of pups, and a decrease was observed in the number of pups born in the experimental group. Maternal weight, litter weight, and individual pup weight were not different between the control and experimental groups. Maternal periodontitis impaired reproductive performance in the F1 generation. We showed that periodontitis may induce reproductive injury in adult offspring even if the offspring do not undergo any inflammatory/infectious process during their postnatal life or during gestation. These findings reinforce the importance of oral care during pregnancy.(AU)
Existem evidências substanciais de uma relação direta entre periodontite em mulheres grávidas com efeitos adversos reprodutivos. No entanto, nenhum estudo avaliou os efeitos intergeracionais da periodontite sobre o desempenho reprodutivo das gerações subsequentes. O presente estudo investigou se a doença periodontal materna exerce efeitos intergeracionais deletérios sobre o desempenho reprodutivo em ratos fêmeas da geração F1. Assim, filhas de ratas cujas mães foram submetidas a periodontite experimental ou falsamente operadas foram acasaladas com ratos machos sexualmente experientes. O peso corporal e desempenho reprodutivo da geração F1 foram avaliados no dia 21 de gestação, incluindo o peso materno, peso da ninhada, peso da individual dos filhotes, número de filhotes e de reabsorções. A percentagem de fêmeas com reabsorção e o peso da ninhada/número de filhotes também foram calculados. Comparados com o grupo controle, observou-se aumento na porcentagem e número de reabsorções e no peso da ninhada/ número de filhotes, e decréscimo no número de filhotes nascidos no grupo experimental. O peso materno, peso da ninhada e individual dos filhotes não foi diferente entre o controle e experimental. Estes resultados mostram que a periodontite experimental materna prejudica o desempenho reprodutivo da geração F1, mesmo que estes animais não tenham sido expostos diretamente a um processo inflamatório.(AU)