α-GalCer regulates acute stress-induced steroidogenesis by modulating lipid metabolism in female BALB/c mice

The immune system orchestrates the hypothalamus-pituitary-adrenal (HPA) axis response to stress. However, the impact of invariant natural killer T (iNKT) cell activation on stress-induced glucocorticoid levels remains poorly understood. Alpha-galactosylceramide (α-GalCer), a specific agonist for iNKT cells, activates iNKT cells to produce inflammatory cytokines including interleukin (IL)-4 and interferon (IFN)-γ. Our findings indicate that treatment with α-GalCer 3 hours before acute restraint stress suppressed the elevation of adrenocorticotropic hormone (ACTH) but did not affect the increase in corticosterone (CORT) in mice. However, treatment with α-GalCer 24 hours prior to restraint stress did not alter the rise in ACTH but reduced the increase in CORT by about half. This dissociation between stress-induced ACTH and CORT levels suggests an intra-adrenal regulation of HPA axis responses to acute stress following α-GalCer treatment. We further found that administration of α-GalCer enhances lipid utilization within adrenocortical cells and elicits a hyperresponsive reaction to ACTH stimulation. Mechanistically, IL-4 elevates the expression of type II 3β-hydroxysteroid dehydrogenase/isomerase (HSD3B2) and scavenger receptor class B type I (SRBI) protein in adrenocortical cells, thereby facilitating ACTH-induced glucocorticoid release. Additionally, we observed that acute stress amplifies both α-GalCer-induced IL-4 and IFN-γ production as well as liver injury. Our findings not only elucidate the mechanistic basis underlying interactions between immunity and stress but also highlight potential targets for therapeutic intervention.