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NRI AT 20: NEUROIMMUNOLOGY

The complement cascade repurposed in the brain

Nature Reviews Immunology volume 21, pages 624–625 (2021)Cite this article

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Over the past two decades it has become clear that the complement cascade — best known for its roles in innate immunity and in the clearance of pathogens and immune complexes — has distinct functions in the brain, in both healthy development and in disease. Surprisingly, complement proteins were shown to be abundant in the central nervous system (CNS), and this led to the discovery of non-inflammatory functions for complement in regulating structural plasticity and functional homeostasis of synapses in the developing brain. For example, our study was among the first to implicate C1q and downstream C3 in synaptic pruning (Stevens et al., 2007), a process in which subsets of synapses are eliminated while the remaining synapses are preserved and strengthened. Studies initiated in the laboratory of the late Ben Barres showed that C1q and C3 are not only widely expressed in the CNS, but localize to subsets of immature synapses in the developing visual system, leading to elimination of these ‘tagged’ axons and synapses.

How are complement-tagged synapses eliminated? We and others subsequently found that microglia mediate synaptic pruning via phagocytosis, recognizing complement-tagged synapses using complement receptors, including CR3 (Schafer et al., 2012). We observed fragments of presynaptic terminals within microglia lysosomes during critical periods of synaptic pruning. Mice lacking C3 or CR3 showed reduced synaptic pruning, indicating that deficient complement signalling during brain development results in long-term defects in synaptic connectivity. Later, we and others characterized additional immune-related pathways — including the CD47–SIRPα ‘don’t-eat-me’ signal — that also regulate microglial pruning of synapses, helping to determine which are preserved and which are eliminated (Lehrman et al., 2018).

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References

Original articles

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Authors and Affiliations

  1. F.M. Kirby Center for Neurobiology, Boston Children’s Hospital, Boston, MA, USA

    Beth Stevens & Matthew B. Johnson

  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Beth Stevens & Matthew B. Johnson

  3. Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA

    Beth Stevens & Matthew B. Johnson

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  1. Beth Stevens
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  2. Matthew B. Johnson
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Correspondence to Beth Stevens.

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B.S. is on the Advisory Board of Annexon Biosciences.

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Stevens, B., Johnson, M.B. The complement cascade repurposed in the brain. Nat Rev Immunol 21, 624–625 (2021). https://doi.org/10.1038/s41577-021-00621-z

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