He, Danyang, Xu, Heping, Zhang, Huiyuan, Tang, Ruihan, Lan, Yangning, Xing, Ruxiao, Li, Shaomin, Christian, Elena, Hou, Yu, Lorello, Paul, Caldarone, Barbara, Ding, Jiarui, Nguyen, Lan, Dionne, Danielle, Thakore, Pratiksha, Schnell, Alexandra, Huh, Jun R., Rozenblatt-Rosen, Orit, Regev, Aviv, and Kuchroo, Vijay K.
To accommodate the changing needs of the developing brain, microglia must undergo substantial morphological, phenotypic, and functional reprogramming. Here, we examined whether cellular metabolism regulates microglial function during neurodevelopment. Microglial mitochondria bioenergetics correlated with and were functionally coupled to phagocytic activity in the developing brain. Transcriptional profiling of microglia with diverse metabolic profiles revealed an activation signature wherein the interleukin (IL)-33 signaling axis is associated with phagocytic activity. Genetic perturbation of IL-33 or its receptor ST2 led to microglial dystrophy, impaired synaptic function, and behavioral abnormalities. Conditional deletion of Il33 from astrocytes or Il1rl1 , encoding ST2, in microglia increased susceptibility to seizures. Mechanistically, IL-33 promoted mitochondrial activity and phagocytosis in an AKT-dependent manner. Mitochondrial metabolism and AKT activity were temporally regulated in vivo. Thus, a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis supports microglial metabolic adaptation and phagocytic function during early development, with implications for neurodevelopmental and neuropsychiatric disorders. [Display omitted] • Phagocytic activity and bioenergetics are coupled in microglia during development • Astrocyte-derived IL-33 promotes microglial engulfment and bioenergetics via AKT • Loss of ST2 and IL-33 results in microglial dysfunction and susceptibility to seizures • Microglial mitochondrial metabolism and AKT activity are temporally regulated in vivo Microglia are capable of diverse functions to accommodate the changing needs of the central nervous system during development. He et al. define a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis that supports microglial metabolic adaptation and phagocytic function during early development, with implications for neurodevelopmental and neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]