Nature: East is not bright and West is bright! Immune activation during pregnancy can blunt adult microglia and strengthen the immunity of star gum

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As brain immune cells, the main function of microglia is rapid immune activation to protect the brain, and microglia have a significant impact on
neurons after immune activation dysfunction.
Mother mice are injected with the Toll-like receptor 3 (TLR3) agonist poly (I:C) to establish a model of maternal immune activation, with a rise in serum interleukin 6 (IL-6), which may have a lifelong effect on
the neurodevelopment of offspring mice.

There is a paradox in the clinic: cytokine levels in the cerebrospinal fluid of patients with schizophrenia increase, but brain imaging data show that cellular immune activation is not only not enhanced, but decreased
.

On September 29, 2022, the team of Akira Sawa in the Department of Neuroscience of Solomon Snyder of Johns Hopkins University School of Medicine revealed that maternal immunity activates adult offspring microglia with decreased immune activity, but enhances astrocyte activity
.

1

Immunoactivity of adult microglia after early immune stress is low

In order to study the immune response of maternal immune activation (MIA) to its offspring in adulthood, the control group and MIA mice received physiological saline and lipopolysaccharide injections respectively after adulthood, and found that most of the mouse microglial differential expression genes caused by LPS were expressed down-regulated in MIA mice, especially the inherent immune infectious interferon signaling pathway
.

LPS causes control microglia to express downregulated genes, which is attenuated in MIA model mice
.
These results indicate that microglial activity decreases in mice, progeny model mice of the MIA model as
adults.
This decrease in activity has the presence of the cortex and the striatum, but the striatal region is more pronounced
.

Immunofluorescence experiments found that compared with the control group, microglia in the striatal region became smaller in size and weakened in phagocytosis after LPS inflammatory stimulation, which further showed that MIA "passivated" the immune ability of progeny microglia
.

Figure 1: Early infection causes low activity of adult microglia

2

Microglial immune activity is low on the following genetic mechanisms

Sequencing of chromatin transponase accessibility found that 97% of chromatin open areas in subgenerated adult mice of the MIA model became more open
.
More specifically, about 83 transcription factors exist in the MIA model and control group of mouse microglia with different occupancies, of which 76% MIA microglia have lower transcription factor occupancy than the control group, including the important transcription factors GATA4, SMAD3, and STAT1
, which regulate the interferon immune response.

According to the single-cell sequencing technique, the above-mentioned immunopassivated microglia in MIA offspring adult mice can be divided into 11 subgroups, of which the number of ccl3-positive pro-inflammatory cell populations is significantly reduced
.

Figure 2: MIA model mouse chromatin open region

3

Passivate the gum, strengthen the star glue

Simultaneous administration of a collective stimulator 1 receptor (CSF1R) inhibitor during maternal immune activation achieves brief clearance of microglia, and LPS inflammation stimulates microglia that reproduce in adulthood does not show passivated immune activation: ccl3-positive pro-inflammatory cell population increases
.
MIA offspring adult mouse microglia decreased TNFα protein levels after receiving LPS stimulation, but no decrease
in TNFα protein levels occurred in the above regenerated microglia.

MIA offspring adult mouse microglia decreased IL-6 protein levels after receiving LPS stimulation, but the IL-6 protein of surrounding astrocytes and neurons was elevated, and the pathological changes
of astrocytes in astrocytes were alleviated after brief clearance of embryonic microglia in MIA model mice.

Electrophysiological experiments found that the tiny excitatory postsynaptic current of dopamine type 2 receptor neurons in the ventral striatal region of adult offspring mice in the MIA model was weakened, and the paired pulse ratio (PPR) increased, while the electrical activity of dopamine type 1 receptor neurons did not occur with this abnormality
.
Clearance of embryonic microglia in MIA model mice can significantly alleviate dysfunction
of dopamine type 2 receptor neurons.

Figure 3: Clearance of embryonic stage "passivated" microglia

summary

In this paper, it is found that after experiencing early pregnancy infection stress, the immune activity of microglia in the brain of mice in adulthood is low, but it promotes the immune activity of peripheral astrocytes and striatal neural circuit disorders
.

【References】

1.
Hayes, L.
N.
, An, K.
, Carloni, E.
 et al.
 Prenatal immune stress blunts microglia reactivity, impairing neurocircuitry.
 Nature (2022).
https://doi.
org/10.
1038/s41586-022-05274-z

The images in the article are from references