Astrocyte-derived Interleukin-33 promotes microglial synapse engulfment and neural circuit development Ilia D. Vainchtein1, Gregory Chin1, Frances S. Cho5,7, Kevin W. Kelley1, John G. Miller1, Elliott C. Chien1, Shane A. Liddelow8, Phi T. Nguyen1,6, Hiromi Nakao-Inoue1, Leah C. Dorman1,5, Omar Akil3, Satoru Joshita9, Ben A. Barres10, Jeanne T. Paz4,7, Ari B. Molofsky2, Anna V. Molofsky1 1Departments of Psychiatry/Weill Institute for Neurosciences, 2Laboratory Medicine 3Otolaryngology, 4Neurology, 5Neuroscience Graduate Program, and 6Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA; 7Gladstone Institute of Neurological Disease, San Francisco, CA, USA; 8Neuroscience Institute and Department of Neuroscience and Physiology, NYU Langone Medical School, New York, NY, USA; 9Research Center for Next Generation Medicine, Shinshu University, Matsumoto, Japan; 10Department of Neurobiology, Stanford University, Palo Alto, CA, USA
Neuronal synapse formation and remodeling is essential to central nervous system (CNS) development and dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this impacts CNS synapses is largely unknown. We found that IL-1 family cytokine Interleukin-33 (IL-33) is induced in developing astrocytes during postnatal synapse maturation, and that loss of astrocyte-derived IL-33 or the IL-33 receptor leads to excess neuronal synapses and altered neural circuit function. IL-33 signals primarily to microglia and is required for physiologic microglial immune activation. It promotes microglial synapse engulfment, thereby driving microglial-dependent synapse depletion in vivo. We conclude that astrocyte-derived IL-33 promotes physiologic microglial function and neural circuit development, revealing a novel innate immune mechanism required for synapse remodeling and CNS development. Future work will examine the transcriptomic changes induced by IL-33 in microglia in order to determine the molecular mechanism by which it promotes engulfment of synapses.
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