Anthony Vitale

Background: Maternal immune activation (MIA), often triggered by infection or severe inflammatory stress during pregnancy, is an established environmental risk factor for neurodevelopmental disorders in offspring, including autism spectrum disorder (ASD) and schizophrenia.¹˒² Interleukin-6 (IL-6) has emerged as a central mediator of this process, capable of altering placental function, reaching the fetal compartment, and disrupting cytokine-mediated programs essential to early brain formation.²˒³ Despite this association, the precise mechanisms by which maternal cytokines traverse the placental barrier and produce lasting structural and behavioral consequences remain incompletely understood.¹

Objective: This narrative review examined how maternal IL-6 is transported across the placental interface, how that signal alters fetal neural progenitor cell biology, and how these mechanistic findings translate to neurodevelopmental and behavioral outcomes in animal models and humans.¹˒⁵

Search Methods: Literature was identified through PubMed using the following keywords: “maternal immune activation,” “interleukin-6,” “placenta-on-a-chip,” “neural progenitor cells,” “neurogenesis,” “gliogenesis,” “JAK/STAT3,” “amygdala connectivity,” and “neurodevelopmental disorders.” Studies published between 2017 and 2025 were prioritized.

Results: A placenta-on-a-chip (PoC) model composed of human trophoblast (JEG-3) and endothelial (HUVEC) cells cultured on a 0.4 µm porous membrane under continuous perfusion reproduced key features of the human placental barrier.¹ This system demonstrated selective transport behavior, including free passage of small molecules like caffeine, active restriction of larger compounds such as glyburide via BCRP efflux transporters, and IL-6 infiltration at rates exceeding what was previously estimated.¹ Downstream of placental transfer, human neural progenitor cells (NPCs) were shown to respond to IL-6 through soluble receptor-mediated trans-signaling, activating gp130, JAK1, and STAT3 at the Y705 residue.² Western blot analysis confirmed significant increases in phosphorylated STAT3 following acute IL-6 exposure (P < 0.0036), and RNA sequencing identified radial glia as the most vulnerable cell type, exhibiting upregulation of immune-related genes including MHCI and NR2F1, and downregulation of protein translation machinery.² These transcriptomic alterations redirected progenitor fate from neurogenesis toward gliogenesis, mirroring molecular stress signatures found in clinical ASD brain tissue.² Animal studies demonstrated that even modest perinatal IL-6 elevation reduced neural stem cell and progenitor output by approximately 50%, with corresponding decreases in hippocampal neurogenesis, amygdala astrogliogenesis, and corpus callosum oligodendrogenesis.³ Adult offspring exhibited persistent behavioral abnormalities including loss of social preference, a 50% reduction in ultrasonic vocalizations, and a 50% increase in repetitive self-grooming.³ At the circuit level, behavioral deficits in MIA offspring were linked to hyperactivity in the primary somatosensory cortex dysgranular zone (S1DZ), and IL-17a was shown to act directly on IL-17Ra-expressing neurons in this region to reduce firing rates and rescue sociability in both MIA and monogenic models.⁴ Clinical translation of these findings was established in a prospective cohort of 86 human mother-infant pairs, in which higher maternal IL-6 concentrations during pregnancy were associated with larger right amygdala volume in newborns, stronger bilateral amygdala connectivity to sensory and salience networks, and lower impulse control assessed by snack delay task at age 2.⁵

Conclusion: Evidence across placental, cellular, animal, and human cohort studies supports a unified model in which maternal IL-6 crosses or amplifies signaling at the placental barrier, reprograms fetal neural progenitors through JAK/STAT3-dependent pathways, and produces lasting alterations in brain structure, circuit function, and behavior.¹˒²˒³˒⁵ Placenta-on-a-chip platforms represent a promising translational tool for quantifying cytokine transport, screening interventions that may limit harmful fetal exposure, and evaluating the safety of IL-6 pathway inhibitors such as tocilizumab during pregnancy.¹ These findings establish maternal inflammatory status as a prospective determinant of fetal neurodevelopment and a critical target for prevention and early clinical risk stratification.⁴˒⁵

Works Cited

1. Pemathilaka RL, Alimoradi N, Reynolds DE, Hashemi NN. Transport of Maternally Administered Pharmaceutical Agents Across the Placental Barrier In Vitro. ACS Appl Bio Mater. 2022;5(5):2273-2284. doi:10.1021/acsabm.2c00121
2. Sarieva K, Hildebrand F, Kagermeier T, Yentür Z, Becker K, Mayer S. Pluripotent stem cell-derived neural progenitor cells can be used to model effects of IL-6 on human neurodevelopment. Dis Model Mech. 2023;16(11):dmm050306. doi:10.1242/dmm.050306
3. Velloso FJ, Wadhwa A, Kumari E, Carcea I, Gunal O, Levison SW. Modestly increasing systemic interleukin-6 perinatally disturbs secondary germinal zone neurogenesis and gliogenesis and produces sociability deficits. Brain Behav Immun. 2022;101:23-36. doi:10.1016/j.bbi.2021.12.015
4. Reed MD, Yim YS, Wimmer RD, et al. IL-17a promotes sociability in mouse models of neurodevelopmental disorders. 2020;577(7789):249-253. doi:10.1038/s41586-019-1843-6
5. Graham AM, Rasmussen JM, Rudolph MD, et al. Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age. Biol Psychiatry. 2018;83(2):109-119. doi:10.1016/j.biopsych.2017.05.027