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Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation

Danyang He1, Heping Xu2, Huiyuan Zhang3

  • 1Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Institute of Basic Medical Science, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Immunity
|January 4, 2022
PubMed

Insights

Microglia adapt their metabolism to support brain development. A signaling circuit involving interleukin-33 (IL-33) and AKT promotes microglial function, impacting neurodevelopmental disorders.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Developmental Biology

Background:

  • Microglia, the brain's immune cells, must adapt to support the developing brain.
  • Cellular metabolism is crucial for cell function, but its role in developing microglia is not fully understood.

Purpose of the Study:

  • To investigate the role of cellular metabolism in regulating microglial function during neurodevelopment.
  • To elucidate the signaling pathways involved in microglial metabolic adaptation.

Main Methods:

  • Analysis of microglial mitochondrial bioenergetics and phagocytic activity in the developing brain.
  • Transcriptional profiling of microglia with varying metabolic states.
  • Genetic manipulation of the interleukin-33 (IL-33) signaling pathway (IL-33, ST2) and AKT signaling.
  • In vivo assessment of microglial function, synaptic activity, and behavior.

Main Results:

  • Microglial mitochondrial function correlated with phagocytic activity.
  • An IL-33-ST2 signaling axis was identified, linked to microglial activation and phagocytosis.
  • Disruption of IL-33-ST2 signaling caused microglial dystrophy, impaired synaptic function, and behavioral deficits.
  • Conditional deletion of IL-33 or ST2 increased seizure susceptibility.
  • IL-33 promoted mitochondrial activity and phagocytosis via AKT signaling, which was temporally regulated.

Conclusions:

  • A microglia-astrocyte circuit mediated by IL-33-ST2-AKT signaling is essential for microglial metabolic adaptation and phagocytosis during early brain development.
  • This pathway has significant implications for understanding and potentially treating neurodevelopmental and neuropsychiatric disorders.
Keywords:
IL-33bioenergeneticsmicroglianeurodevelopmentphagocytosisseizuresynapse

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