IL-33 modulates maternal–fetal macrophage immunometabolism and is associated with attenuation of MIA-associated behavioral abnormalities in adult offspring

Maternal immune activation (MIA) is a pivotal risk factor for neurodevelopmental disorders, including autism spectrum disorder. However, the mechanisms of MIA at the maternal–fetal interface remain elusive. Here, we used soluble tachyzoite antigen (STAg) from Toxoplasma gondii to induce MIA in pregnant mice at E14.5, followed by maternal administration of interleukin-33 (IL-33) from E15.5 to E17.5. Proteomic profiling coupled with protein-protein interaction network analysis nominated IL-33 as a candidate immunoregulatory factor. In exploratory analyses, maternal IL-33 administration was associated with shifts in macrophage-associated immune profiles, reduced placental inflammation, and attenuated MIA-associated behavioral abnormalities in adult offspring. Given that suppression of tumorigenicity 2 (ST2) is the cognate receptor for IL-33, we next interrogated this pathway in ST2-deficient mice. ST2 deficiency abolished the effects of IL-33 on macrophage repolarization and inflammatory homeostasis, and the behavioral improvements were not evident in ST2-deficient offspring. Mechanistically, IL-33 administration was associated with reduced glycolytic features and improved mitochondrial function in macrophages, consistent with partial restoration of immunometabolic homeostasis at the maternal–fetal interface. Collectively, our findings highlight an immunometabolic axis in STAg-induced MIA pathogenesis, revealing IL-33/ST2 signaling as a potential experimental target for mitigating MIA-associated immune and behavioral abnormalities.