Astrocyte-derived Interleukin-33 promotes microglial synapse engulfment and neural circuit development I

Neuronal synapse formation and remodeling is essential to central nervous system (CNS) development and is dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this impacts CNS synapses is largely unknown. Here we show that the IL-1 family cytokine Interleukin-33 (IL-33) is produced by developing astrocytes and is developmentally required for normal synapse numbers and neural circuit function in the spinal cord and thalamus. We find that IL-33 signals primarily to microglia under physiologic conditions, that it promotes microglial synapse engulfment, and that it can drive microglial-dependent synapse depletion in vivo. These data reveal a cytokine-mediated mechanism required to maintain synapse homeostasis during CNS development. 16 samples total consisting of 4 biological replicates per group of flow sorted IL-33pos and neg astrocytes from thalamus or spinal cord at P15 (IL-33mCherry reporter from M. Colonna lab)