The placental interleukin-6 signaling controls fetal brain development and behavior

Abstract

Epidemiological studies show that maternal immune activation (MIA) during pregnancy is a risk factor for autism. However, mechanisms for how MIA affects brain development and behaviors in offspring remain poorly described. To determine whether placental interleukin-6 (IL-6) signaling is required for mediating MIA on the offspring, we generated mice with restricted deletion of the receptor for IL-6 (IL-6Rα) in placental trophoblasts (Cyp19-Cre+;Il6rafl/fl), and tested offspring of Cyp19-Cre+;Il6rafl/fl mothers for immunological, pathological and behavioral abnormalities following induction of MIA. We reveal that MIA results in acute inflammatory responses in the fetal brain. Lack of IL-6 signaling in trophoblasts effectively blocks MIA-induced inflammatory responses in the placenta and the fetal brain. Furthermore, behavioral abnormalities and cerebellar neuropathologies observed in MIA control offspring are prevented in Cyp19-Cre+;Il6rafl/fl offspring. Our results demonstrate that IL-6 activation in placenta is required for relaying inflammatory signals to the fetal brain and impacting behaviors and neuropathologies relevant to neurodevelopmental disease.

Altered Hippocampal Gene Expression and Morphology in Fetal Piglets following Maternal Respiratory Viral Infection

“…While transplacental fetal infection does occur, there was no significant effect of positive viral infection on any analyses in our model. Epidemiological studies assessing the risks from maternal infection for psychiatric disorders in offspring indicate that both pathogens which are transmissible to the fetus (rubella virus, cytomegalovirus, herpes simplex virus, and Toxoplasma gondii ) and those that are nontransmissible (influenza virus) confer a risk [2, 66]; animal models strongly suggest that the maternal inflammatory response (i.e., cytokines such as IL-6 and IL-17a), and not the pathogen, drives the detrimental effects of MIA on the neurodevelopment and behavior of the offspring [13, 14, 19]. Thus, in our model, PRRSV infection serves to activate a maternal immune response comparable to that observed during human viral infections, such as influenza.…”

“…Indeed, Wu et al [14] and Mouihate and Mehdawi [15] demonstrated an increased expression of IL-6, STAT3, and pSTAT3 in the fetal brain in the immediate hours following MIA, though these studies did not extend past 24 h after MIA induction. In fact, the most compelling and comprehensive evidence of the impact of MIA on fetal brain gene and protein expression to date has focused on the immediate time points following immune activation [19, 90], and several studies support the idea that neuroinflammation is resolved by the neonatal and postnatal periods [79, 81, 91].…”

“…Smith et al [13] demonstrated, through inhibition or injection of recombinant IL-6 into pregnant dams, the critical involvement of this particular cytokine in mediating behavioral abnormalities in murine offspring. A potential mechanism through which IL-6 accesses the fetal compartment was revealed by Wu et al [14], who performed a restricted deletion of the IL-6 receptor on placental trophoblasts to prevent the neurodevelopmental pathologies caused by MIA. In the brain of fetuses exposed to maternal lipopolysaccharide (LPS) treatment, intracellular IL-6 signaling, through signal transducer and activator of transcription 3 (STAT3), is increased and can be blunted by IL-6-blocking antibody [14, 15].…”

“…A potential mechanism through which IL-6 accesses the fetal compartment was revealed by Wu et al [14], who performed a restricted deletion of the IL-6 receptor on placental trophoblasts to prevent the neurodevelopmental pathologies caused by MIA. In the brain of fetuses exposed to maternal lipopolysaccharide (LPS) treatment, intracellular IL-6 signaling, through signal transducer and activator of transcription 3 (STAT3), is increased and can be blunted by IL-6-blocking antibody [14, 15]. A series of elegant studies done in a rodent maternal polyinosinic:polycytidylic acid (poly I:C) model revealed that IL-6 may also be driving T-helper-cell development and activation, augmenting IL-17a release [16].…”

Progress in the understanding of the etiology and predictability of fetal growth restriction

“…BPH/5, a mouse model with mild hypertension, revealed abnormal placentation, FGR, excessive C3 deposition and neutrophil infiltration in the ectoplacental cone at E6.5 and E8.5 respectively, consistent with reduced levels of VEGF in the placenta and enhanced levels of TNF-α released by neutrophils (Gelber et al 2015). In addition, activation of mouse maternal innate immune system by intravenous administration of polyinosinic-polycytidylic acid (poly(I:C)), a nonpathogenic antigen, caused cerebellar neuropathology and behavioral abnormalities in the offspring, which were mediated by an increased IL-6 signaling in the placenta (Wu et al 2017).…”