Maternal immune activation induced by lipopolysaccharide triggers immune response in pregnant mother and fetus, and induces behavioral impairment in adult rats

Simões, Lutiana R.; Sangiogo, Gustavo; Tashiro, Michael Hikaru; Generoso, Jaqueline S.; Faller, Cristiano Julio; Dominguini, Diogo; Mastella, Gustavo Antunes; Scaini, Giselli; Giridharan, Vijayasree V.; Michels, Monique; Florentino, Drielly; Petronilho, Fabrícia; Réus, Gislaine Z.; Dal‐Pizzol, Felipe; Zugno, Alexandra I.; Barichello, Tatiana

doi:10.1016/j.jpsychires.2018.02.007

Cited by 58 publications

(53 citation statements)

References 71 publications

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“…It is well‐known that the blood–brain barrier (BBB) is structurally important in protecting the developing fetal brain from outside insults (Goasdoue, Miller, Colditz, & Bjorkman, 2017), so it may play a role in blocking fetal brain inflammation following LPS‐induced IUI. However, evidence shows that LPS can be found in the fetus after intrauterine injection of FITC‐conjugated LPS (Brown, Maubert, Anton, Heiser, & Elovitz, 2019) or intravenous injection of 125 I ‐LPS (Kohmura, Kirikae, Kirikae, Nakano, & Sato, 2000), and that LPS has been shown to compromise the integrity of the fetal blood brain barrier as early as 6 hr postexposure in pregnant rats (Simoes et al., 2018). Therefore, it is likely that in mouse models LPS introduced via intrauterine injection can circulate into the fetal brain, disrupt the structure or function of the BBB, and ultimately cause damage to the fetal brain by interacting with its receptor TLR4 (Ernst, Gonzalez, Ofori, & Elovitz, 2010).…”

Section: Discussionsupporting

confidence: 88%

The effect of intrauterine inflammation on mTOR signaling in mouse fetal brain

Dong

Lei

Elsayed

et al. 2020

Developmental Neurobiology

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Fetuses exposed to an inflammatory environment are predisposed to long‐term adverse neurological outcomes. However, the mechanism by which intrauterine inflammation (IUI) is responsible for abnormal fetal brain development is not fully understood. The mechanistic target of rapamycin (mTOR) signaling pathway is closely associated with fetal brain development. We hypothesized that mTOR signaling might be involved in fetal brain injury and malformation when fetuses are exposed to the IUI environment. A well‐established IUI model was utilized by intrauterine injection of lipopolysaccharide (LPS) to explore the effect of IUI on mTOR signaling in mouse fetal brains. We found that microglia activation in LPS fetal brains was increased, as demonstrated by elevated Iba‐1 protein level and immunofluorescence density. LPS fetal brains also showed reduced neuronal cell counts, decreased cell proliferation demonstrated by low Ki67‐positive density, and elevated neuron apoptosis evidenced by high expression of cleaved Caspase 3. Furthermore, we found that mTOR signaling in LPS fetal brains was elevated at 2 hr after LPS treatment, declined at 6 hr and showed overall inhibition at 24 hr. In summary, our study revealed that LPS‐induced IUI leads to increased activation of microglia cells, neuronal damage, and dynamic alterations in mTOR signaling in the mouse fetal brain. Our findings indicate that abnormal changes in mTOR signaling may underlie the development of future neurological complications in offspring exposed to prenatal IUI.

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Section: Discussionsupporting

confidence: 88%

The effect of intrauterine inflammation on mTOR signaling in mouse fetal brain

Dong

Lei

Elsayed

et al. 2020

Developmental Neurobiology

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“…Divergent lines of evidence suggest important functional implications of Th17 cells in schizophrenia pathophysiology, psychopathology, and treatment response . Maternal immune activation (MIA) has consistently been linked to enhanced risk of schizophrenia in offspring by both experimental animal and epidemiological studies . Interestingly, maternal immune stimulation during pregnancy was shown to shape the immunological phenotype of offspring, especially through preferential development of Th17 cells .…”

Section: Discussionmentioning

confidence: 99%

Impact of antipsychotic medication on IL‐6/STAT3 signaling axis in peripheral blood mononuclear cells of drug‐naive schizophrenia patients

Subbanna

Shivakumar

Venugopal

et al. 2019

Psychiatry Clin Neurosci

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Aim: Immunopathogenesis remains a widely appreciated etiopathological model of schizophrenia. Persistent efforts have aimed to identify schizophrenia biomarkers indexing immune system abnormalities and also immuno-dampening effects of antipsychotic medications. Although data arising from published reports are encouraging, such studies are limited to a few immune parameters and not focused on a specific pathway. Th17 cells-mediated immuno-inflammatory responses have emerged as a potential mechanism in various neuropsychiatric conditions, including schizophrenia. The Th17 pathway is distinctly regulated through a coordinated action of multiple cytokines and transcription factors. In this study, we explored whether antipsychotic medication has any effect on the cytokines and transcription factors of the Th17 pathway.Methods: A total of 27 drug-naive schizophrenia patients were recruited and followed up for 3 months after initiation of antipsychotic medication. Lymphocyte gene expression levels of two transcription factors (STAT3 and RORC) and one of their upstream regulators, IL6, were quantified before and after treatment. Plasma levels of cytokines, such as interleukin (IL)-1β, IL-6, IL-17A, IL-23, and IL-33, were also analyzed before and after treatment.Results: Treatment with antipsychotic medication for 3 months resulted in significant downregulation of STAT3 gene expression as well as reduction in plasma levels of IL-1β, IL-6, and IL-17A. Significant reduction in total scores for the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms was also observed in schizophrenia patients after 3 months of antipsychotic treatment. Conclusion:Our findings suggest possible immunomodulatory effects of antipsychotic medication on the critical regulators, such as IL-6 and STAT3, of the Th17 pathway in schizophrenia patients. The IL-6/STAT3 signaling axis involved in the transcriptional regulation of Th17 cells might appear as an important target of antipsychotic treatment in schizophrenia patients. Alternatively, irrespective of the effect of antipsychotic drugs, the IL-6/STAT3 signaling axis might be crucially involved in ameliorating psychotic symptoms.Schizophrenia is a complex neurodevelopmental disorder with inadequately explained etiopathology. The notion that schizophrenia is a multisystem disorder has gained momentum in recent times. In addition to abnormalities in the central nervous system (CNS), immune system dysfunction has persistently been implicated in schizophrenia pathophysiology based on the data derived from genomic, transcriptomic, and proteomic studies. 1-3 The strength of this connection has further been enhanced by studies on schizophrenia showing close cross talk between the immune system and other pathologically relevant systems or pathways, such as the CNS, cardiovascular system, metabolic system, and the hypothalamicpituitary-adrenal axis.Altered expressions of immune parameters in the cerebrospinal fluid and post-mortem brain as well as findings correlating i...

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“…Bacterial infections have a high prevalence in women of reproductive age. Increasing evidence indicates that modifications of the “in utero” environment due to maternal bacterial infection can result in cognitive and behavioral disorders in pre‐ or adult offspring, such as impairments in spatial learning and memory (Batinic et al, ; Chlodzinska, Gajerska, Bartkowska, Turlejski, & Djavadian, ; Glass, Norton, Fox, & Kusnecov, ; Simões et al, ) and object recognition (Glass et al, ; Wischhof, Irrsack, Osorio, & Koch, ), increased locomotor activity (Batinic et al, ; Glass et al, ) and anxiety (Enayati et al, ; Glass et al, ; Hsueh et al, ; Penteado et al, ) and decreased prepulse inhibition of acoustic startle (Fortier, Luheshi, & Boksa, ; Glass et al, ; Wischhof et al, ) and social behaviors (Glass et al, ; Hsueh et al, ). Lipopolysaccharide (LPS) injection in the pregnancy is a widely accepted mouse model of maternal bacterial infection.…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide exposure during late embryogenesis triggers and drives Alzheimer‐like behavioral and neuropathological changes in CD‐1 mice

et al. 2020

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Introduction Infections could contribute to Alzheimer's disease (AD) neuropathology in human. However, experimental evidence for a causal relationship between infections during the prenatal phase and the onset of AD is lacking. Methods CD‐1 mothers were intraperitoneally received lipopolysaccharide (LPS) with two doses (25 and 50 μg/kg) or normal saline every day during gestational days 15–17. A battery of behavioral tasks was used to assess the species‐typical behavior, sensorimotor capacity, anxiety, locomotor activity, recognition memory, and spatial learning and memory in 1‐, 6‐, 12‐, 18‐, and 22‐month‐old offspring mice. An immunohistochemical technology was performed to detect neuropathological indicators consisting of amyloid‐β (Aβ), phosphorylated tau (p‐tau), and glial fibrillary acidic protein (GFAP) in the hippocampus. Results Compared to the same‐aged controls, LPS‐treated offspring had similar behavioral abilities and the levels of Aβ42, p‐tau, and GFAP at 1 and 6 months old. From 12 months onward, LPS‐treated offspring gradually showed decreased species‐typical behavior, sensorimotor ability, locomotor activity, recognition memory, and spatial learning and memory, and increased anxieties and the levels of Aβ42, p‐tau, and GFAP relative to the same‐aged controls. Moreover, this damage effect (especially cognitive decline) persistently progressed onwards. The changes in these neuropathological indicators significantly correlated with impaired spatial learning and memory. Conclusions Prenatal exposure to low doses of LPS caused AD‐related features including behavioral and neuropathological changes from midlife to senectitude.

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Maternal immune activation induced by lipopolysaccharide triggers immune response in pregnant mother and fetus, and induces behavioral impairment in adult rats

Cited by 58 publications

References 71 publications

The effect of intrauterine inflammation on mTOR signaling in mouse fetal brain

The effect of intrauterine inflammation on mTOR signaling in mouse fetal brain

Impact of antipsychotic medication on IL‐6/STAT3 signaling axis in peripheral blood mononuclear cells of drug‐naive schizophrenia patients

Lipopolysaccharide exposure during late embryogenesis triggers and drives Alzheimer‐like behavioral and neuropathological changes in CD‐1 mice

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