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Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders

Nature Reviews Immunology volume 21, pages 454–468 (2021)Cite this article

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Abstract

The immune and nervous systems have unique developmental trajectories that individually build intricate networks of cells with highly specialized functions. These two systems have extensive mechanistic overlap and frequently coordinate to accomplish the proper growth and maturation of an organism. Brain resident innate immune cells — microglia — have the capacity to sculpt neural circuitry and coordinate copious and diverse neurodevelopmental processes. Moreover, many immune cells and immune-related signalling molecules are found in the developing nervous system and contribute to healthy neurodevelopment. In particular, many components of the innate immune system, including Toll-like receptors, cytokines, inflammasomes and phagocytic signals, are critical contributors to healthy brain development. Accordingly, dysfunction in innate immune signalling pathways has been functionally linked to many neurodevelopmental disorders, including autism and schizophrenia. This review discusses the essential roles of microglia and innate immune signalling in the assembly and maintenance of a properly functioning nervous system.

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Fig. 1: Microglia influence a number of neurodevelopmental processes.
Fig. 2: AIM2 inflammasome signalling contributes to CNS cell dieback.
Fig. 3: Phagocytic signalling underlies synaptic pruning.
Fig. 4: Maternal immune activation promotes abnormal brain development and autism-like behaviours.

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Acknowledgements

We apologize to authors whose work could not be referenced in this review due to space limitations. We thank members of the Lukens lab and the Center for Brain Immunology and Glia (BIG) for valuable discussions. This work was supported by The National Institutes of Health/National Institute of Neurological Disorders and Stroke (R01NS106383; awarded to J.R.L.), The National Institutes of Health/National Institute of Mental Health (R21MH120412-01; awarded to J.R.L.), The Simons Foundation Autism Research Initiative (Pilot Award 515305 to J.R.L.), and The Owens Family Foundation (Awarded to J.R.L.). K.E.Z. was supported by a Cell and Molecular Biology Training Grant (T32GM008136).

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Authors and Affiliations

  1. Department of Neuroscience, Center for Brain Immunology and Glia (BIG), Charlottesville, VA, USA

    Kristine E. Zengeler & John R. Lukens

  2. Neuroscience Graduate Program, Charlottesville, VA, USA

    Kristine E. Zengeler & John R. Lukens

  3. Cell and Molecular Biology Training Program, School of Medicine, University of Virginia, Charlottesville, VA, USA

    Kristine E. Zengeler & John R. Lukens

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  1. Kristine E. Zengeler
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  2. John R. Lukens
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Correspondence to Kristine E. Zengeler or John R. Lukens.

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Nature Reviews Immunology thanks A. Molofsky and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Axon tract fasciculation

Collective axon growth in a bundle that will eventually constitute a nerve tract.

Segmented filamentous bacteria

A group of commensal bacteria that attach to the ileal epithelium of mice and promote T helper 17 cell development.

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Zengeler, K.E., Lukens, J.R. Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders. Nat Rev Immunol 21, 454–468 (2021). https://doi.org/10.1038/s41577-020-00487-7

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