Microglia, the missing link in maternal immune activation and fetal neurodevelopment; and a possible link in preeclampsia and disturbed neurodevelopment?

Abstract

Disturbances in fetal neurodevelopment have extensively been related to neurodevelopmental disorders in early and later life. Fetal neurodevelopment is dependent on adequate functioning of the fetal immune system. During pregnancy, the maternal immune system is challenged to both tolerate the semi-allogenic fetus and to protect the mother and fetus from microbes. The fetal immune system is influenced by maternal immune disturbances; therefore, perturbations in maternal immunity likely do not only alter pregnancy outcome but also alter fetal neurodevelopment. A possible common pathway could be modulating the functioning of tissue macrophages in the placenta and brain. Maternal immune tolerance towards the fetus involves several complex adaptations. In this active maternal immune state, the fetus develops its own immunity. As cytokines and other players of the immune system -which can pass the placenta- are involved in neurodevelopment, disruptions in immune balance influence fetal neurodevelopment. Several studies reported an association between maternal immune activation, complications of pregnancy as preeclampsia, and altered neonatal neurodevelopment. A possible pathway involves dysfunctioning of microglia cells, the immune cells of the brain. Functionality of microglia cells during normal pregnancy is, however, poorly understood. The recent outbreak of ZIKA virus (ZKV), but also the literature on virus infections in general and its consequences on microglial cell function and fetal neurodevelopment show the devastating effects a virus infection during pregnancy can have.

Environmental Signals on Microglial Function during Brain Development, Neuroplasticity, and Disease

“…It is also known that various cytokines, as well as maternal leukocytes, cross the placental barrier [88]. The recent outbreak of Zika virus (ZIKV) infection in Brazil revealed a series of devastating consequences on fetal neurodevelopment that exemplifies how an environmental component like a virus can cause abnormal neurodevelopment, affecting the fetus's immune system, possibly through changes in the maternal immune function, placental function, and microglia activity [89]. In the same vein, it has been postulated that during maternal infection, fetal microglia can be directly activated by some viruses, or indirectly through cytokines or microchimeric maternal cells [88].…”

“…Moreover, it has been shown that ZIKV invades microglial cells, promoting inflammation, thus disrupting their physiological role during brain development [90]. In addition to ZIKV, other viruses such as cytomegalovirus (CMV) and Rubella also cross the placental barrier and/or BBB and reach the CNS [89]. CMV infection of newborn mice induces a strong inflammatory response in the brain, characterized by microglial activation, recruitment of peripheral immune cells, and the expression of pro-inflammatory cytokines [91].…”

Epigenetics Control Microglia Plasticity

“…In mammals, maternal immune activation, or MIA, which can be due to an inflammatory stimulus like bacterial or viral infections but also activated after allergy during the pregnancy, has been shown to positively correlates with the risk of developing neuropsychiatric disorders like autism in the offspring ( Vogel Ciernia et al, 2018 ). This link may be bridged to an impact of MIA on the microglia from the fetus which leads to the acquisition of functional changes that are maintained in the adult ( Mattei et al, 2017 ; Prins et al, 2018 ; Figure 2D ). In a majority of animal models of maternal immune activation, the rat dams or pregnant mice are treated with either a viral mimetic (poly I:C) or LPS.…”

Callosal septa express guidance cues and are paramedian guideposts for human corpus callosum development

“…The activity of microglia is affected by the maternal immune system and could be activated by a pro‐inflammatory fetal state (Boksa, ; Prins et al. ), leading to an increase in microglial cell number and distribution, as well as their altered morphology. We aimed to limit this effect by selecting samples with no macro‐ or micro‐morphological anomalies, and only fetuses and premature infants with normal prenatal courses up to abortion or premature birth.…”