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

Danyang He; Heping Xu; Huiyuan Zhang; Ruihan Tang; Yangning Lan; Ruxiao Xing; Shaomin Li; Elena Christian; Yu Hou; Paul Lorello; Barbara Caldarone; Jiarui Ding; Lan Nguyen; Danielle Dionne; Pratiksha Thakore; Alexandra Schnell; Jun R Huh; Orit Rozenblatt-Rosen; Aviv Regev; Vijay K Kuchroo

doi:10.1016/j.immuni.2021.12.001

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

Immunity. 2022 Jan 11;55(1):159-173.e9. doi: 10.1016/j.immuni.2021.12.001. Epub 2022 Jan 3.

Authors

Danyang He¹, Heping Xu², Huiyuan Zhang³, Ruihan Tang³, Yangning Lan⁴, Ruxiao Xing⁴, Shaomin Li⁵, Elena Christian⁶, Yu Hou⁷, Paul Lorello⁸, Barbara Caldarone⁸, Jiarui Ding⁶, Lan Nguyen⁶, Danielle Dionne⁶, Pratiksha Thakore⁶, Alexandra Schnell³, Jun R Huh⁹, Orit Rozenblatt-Rosen⁶, Aviv Regev¹⁰, Vijay K Kuchroo¹¹

Affiliations

¹ Evergrande 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. Electronic address: hedanyang@westlake.edu.cn.
² 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; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ 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.
⁵ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁶ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Mouse Behavior Core, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: aregev@broadinstitute.org.
¹¹ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: vkuchroo@rics.bwh.harvard.edu.

Abstract

To accommodate the changing needs of the developing brain, microglia must undergo substantial morphological, phenotypic, and functional reprogramming. Here, we examined whether cellular metabolism regulates microglial function during neurodevelopment. Microglial mitochondria bioenergetics correlated with and were functionally coupled to phagocytic activity in the developing brain. Transcriptional profiling of microglia with diverse metabolic profiles revealed an activation signature wherein the interleukin (IL)-33 signaling axis is associated with phagocytic activity. Genetic perturbation of IL-33 or its receptor ST2 led to microglial dystrophy, impaired synaptic function, and behavioral abnormalities. Conditional deletion of Il33 from astrocytes or Il1rl1, encoding ST2, in microglia increased susceptibility to seizures. Mechanistically, IL-33 promoted mitochondrial activity and phagocytosis in an AKT-dependent manner. Mitochondrial metabolism and AKT activity were temporally regulated in vivo. Thus, a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis supports microglial metabolic adaptation and phagocytic function during early development, with implications for neurodevelopmental and neuropsychiatric disorders.

Keywords: IL-33; bioenergenetics; microglia; neurodevelopment; phagocytosis; seizure; synapse.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal
Disease Susceptibility
Electrical Synapses / metabolism
Energy Metabolism
Humans
Interleukin-1 Receptor-Like 1 Protein / genetics
Interleukin-1 Receptor-Like 1 Protein / metabolism*
Interleukin-33 / genetics
Interleukin-33 / metabolism*
Mice
Mice, Knockout
Microglia / metabolism*
Microglia / pathology
Mitochondria / metabolism*
Neurogenesis / genetics
Oncogene Protein v-akt / metabolism
Phagocytosis
Seizures / immunology*
Signal Transduction

Substances

Il1rl1 protein, mouse
Il33 protein, mouse
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Oncogene Protein v-akt

Grants and funding

R01 AI139536/AI/NIAID NIH HHS/United States