Maternal immune activation in late gestation increases neuroinflammation and aggravates experimental autoimmune encephalomyelitis in the offspring

Zager, Adriano; Peron, Jean Pierre; Mennecier, Gregory; Rodrigues, Sandra; Aloia, Thiago Pinheiro Arrais; Palermo-Neto, João

doi:10.1016/j.bbi.2014.07.021

Cited by 39 publications

(31 citation statements)

References 33 publications

(19 reference statements)

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“…After LPS exposure, the protein levels and immunoreactivity of GFAP (an astrocyte marker) but not Iba1 (a microglial marker) were reported to be increased in neonate brains [52], indicating that glial-neuronal interactions could be altered. However, as a long-term effect in the adulthood offspring, the cell numbers, distributed intensities or the morphology of GFAP-positive astrocytes and of Iba1-positive microglia were identical to controls.…”

Section: Discussionmentioning

confidence: 99%

Expression of cerebral serotonin related to anxiety-like behaviors in C57BL/6 offspring induced by repeated subcutaneous prenatal exposure to low-dose lipopolysaccharide

et al. 2017

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Prenatal exposure to lipopolysaccharide (LPS), which likely occurs due to infection or contact with environmental allergens during pregnancy, is a proposed risk factor that induces anxiety- and autism spectrum disorder-like behaviors in offspring. However, the molecular and behavioral changes in offspring after maternal immune activation have not been completely identified. We hypothesized that a subcutaneous injection of LPS in a pregnant mouse would induce changes in cerebral serotonin (5-HT) in parallel to the appearance of anxiety-like behaviors in the dam’s offspring. After LPS injections (total, 100 μg/Kg), the time spent in the central region during the open field test and the number of times that the mice moved between the light and dark boxes and between the open and closed arms on the elevated plus maze test revealed anxiety-like behaviors in offspring at 5, 6 and 9 weeks of age. The mRNA expression levels of tph2 (5-HT synthesizing enzyme) and slc6a4 (5-HT transporter) were down-regulated in both adolescent (5 weeks of age) and adult (8 weeks of age) brains. Immunohistochemistry revealed that the numbers and sizes of tph2-expressing cells were notably decreased in the raphe nuclei of the midbrain of adults. Moreover, compared with controls (phosphate-buffered saline-treated offspring), the cerebral 5-HT concentration at adolescence and adulthood in LPS-induced offspring was significantly decreased. We concluded that maternal immune activation induced by exposure to a low dose of LPS decreased cerebral 5-HT levels in parallel to the down-regulation of the tph2 and slc6a4 genes and in conjunction with anxiety-like behaviors in offspring.

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Section: Discussionmentioning

confidence: 99%

Expression of cerebral serotonin related to anxiety-like behaviors in C57BL/6 offspring induced by repeated subcutaneous prenatal exposure to low-dose lipopolysaccharide

et al. 2017

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“…While astrocytic production of IL-6 has been used as a surrogate parameter to identify a bona fide pro-inflammatory phenotype in a multitude of experimental studies (24,43,44), surprisingly limited knowledge exists about the functional role of astrocyte-derived IL-6 during EAE and Multiple Sclerosis. While global IL-6 deficient mice are resistant to EAE most likely due to defects in the interplay between innate and adaptive immunity during the priming phase causing failure to raise pathogenic T cell responses (45), recent studies made use of transgenic mice with GFAP-driven expression of IL-6 on a globally IL-6 deficient background (GFAP-IL-6-IL-6 KO mice).…”

Section: Role Of Selected Pro- and Anti-inflammatory Cytokinesmentioning

confidence: 99%

“…This observation was recapitulated in treatment experiments applying LPS to neonatal rats, which decreased pro-inflammatory responses in EAE at later age, as measured by increased IL-10 in the spinal cord (71). However, conflicting results for TLR4 stimulation have been recently published for the treatment of pregnant mice with LPS, which show declined IL-10 production from mixed glial cultures from newborn mice restimulated with LPS(43). …”

Section: Role Of Selected Pro- and Anti-inflammatory Cytokinesmentioning

confidence: 99%

Control of autoimmune CNS inflammation by astrocytes

2015

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Multiple Sclerosis is a neurologic disease caused by immune cell infiltration into the central nervous system, resulting in grey and white matter inflammation, progressive demyelination and neuronal loss. Astrocytes, the most abundant cell population in the CNS, have been considered inert scaffold- or housekeeping cells for many years. However, recently it has become clear that this cell population actively modulates the immune response in the CNS at multiple levels. While being exposed to a plethora of cytokines during ongoing autoimmune inflammation, astrocytes modulate local CNS inflammation by secreting cytokines and chemokines, among other factors. This review article gives an overview of the most recent understanding about cytokine networks operational in astrocytes during autoimmune neuroinflammation and highlights potential targets for immunomodulatory therapies for Multiple Sclerosis.

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“…Microglia activation in the CNS is considered to be a crucial step in development of EAE and contributes to dendritic pathology and neuronal loss by releasing cytokines, such as IL-6, and TNF-α (Centonze et al, 2009; Lassmann, 2014; Trebst et al, 2001; Zager et al, 2015). We, however, did not find increases in mRNA and protein levels of brain IL-6 and TNF-α in IL-17A-in-Brain mice.…”

Section: Discussionmentioning

confidence: 99%

Intracranial delivery of interleukin-17A via adeno-associated virus fails to induce physical and learning disabilities and neuroinflammation in mice but improves glucose metabolism through AKT signaling pathway

Yang

Kou

Lim

et al. 2016

Brain, Behavior, and Immunity

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Interleukin-17A (IL-17A) is generally considered as one of the pathogenic factors involved in multiple sclerosis (MS). Indirect evidence for this is that IL-17A-producing T helper 17 (Th17) cells preferentially accumulate in lesions of MS and experimental autoimmune encephalomyelitis (EAE). However, a direct involvement of IL-17A in MS pathogenesis is still an open question. In this study, we overexpressed IL-17A in the brains of mice (IL-17A-in-Brain mice) via recombinant adeno-associated virus serotype 5 (rAAV5)-mediated gene delivery. In spite of high levels of IL-17A expression in the brain and blood, IL-17A-in-Brain mice exhibit no inflammatory responses and no abnormalities in motor coordination and spatial orientation. Unexpectedly, IL-17A-in-Brain mice show decreases in body weight and adipose tissue mass and an improvement in glucose tolerance and insulin sensitivity. IL-17A enhances glucose uptake in PC12 cells by activation of AKT. Our results provide direct evidence for the first time that IL-17A overexpression in the central nervous system does not cause physical and learning disabilities and neuroinflammation and suggest that IL-17A may regulate glucose metabolism through the AKT signaling pathway.

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Maternal immune activation in late gestation increases neuroinflammation and aggravates experimental autoimmune encephalomyelitis in the offspring

Cited by 39 publications

References 33 publications

Expression of cerebral serotonin related to anxiety-like behaviors in C57BL/6 offspring induced by repeated subcutaneous prenatal exposure to low-dose lipopolysaccharide

Expression of cerebral serotonin related to anxiety-like behaviors in C57BL/6 offspring induced by repeated subcutaneous prenatal exposure to low-dose lipopolysaccharide

Control of autoimmune CNS inflammation by astrocytes

Intracranial delivery of interleukin-17A via adeno-associated virus fails to induce physical and learning disabilities and neuroinflammation in mice but improves glucose metabolism through AKT signaling pathway

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