Interleukin-33 coordinates a microglial phagocytic response and limits corticothalamic excitability and seizure susceptibility

Microglia are key remodelers of neuronal synapses during brain development, but the mechanisms that regulate this process and its ultimate impact on neural circuit function are not well defined. We previously identified the IL-1 family cytokine Interleukin-33 (IL-33) as a novel mediator of microglial synapse remodeling. Here we define the phagocytic program induced in microglia in response to IL-33. We find that IL-33 markedly alters the microglial enhancer landscape and exposes AP-1 transcription factor sites that promote target gene expression. We identify the scavenger receptor MARCO and the pattern recognition receptor TLR2 as downstream mediators of IL-33 dependent synapse engulfment. Conditional deletion of IL-33 in the CNS or its receptor on microglia results in increased numbers of excitatory synapses in the corticothalamic circuit and spontaneous epileptiform activity as well as increased seizure susceptibility by early adulthood. These findings define novel mechanisms through which IL-33 coordinates experience-dependent synaptic refinement to restrict hyperexcitability in the developing brain.