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

Ilia D. Vainchtein(University of California, San Francisco), Gregory Chin(University of California, San Francisco), Frances S. Cho(Gladstone Institutes), Kevin W. Kelley(University of California, San Francisco), John G. Miller(University of California, San Francisco), Elliott C. Chien(University of California, San Francisco), Shane A. Liddelow(Stanford University), Phi T. Nguyen(University of California, San Francisco), Hiromi Nakao-Inoue(University of California, San Francisco), Leah C. Dorman(University of California, San Francisco), Omar Akil(University of California, San Francisco), Satoru Joshita(Shinshu University), Ben A. Barres(Stanford University), Jeanne T. Paz(Gladstone Institutes), Ari B. Molofsky(University of California, San Francisco), Anna V. Molofsky(University of California, San Francisco)
Science
February 1, 2018
10.1126/science.aal3589
Cited by 636Open Access
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Abstract

Neuronal synapse formation and remodeling are essential to central nervous system (CNS) development and are dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this affects CNS synapses is largely unknown. Here, we show that the interleukin-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.

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