Cited by 467Neuroinflammation and Neurodegeneration MechanismsPhagocytosis and Immune RegulationAutophagy in Disease and Therapy

CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

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Pluvinage, John V., Haney, Michael S., Smith, Benjamin A. H., Sun, Jerry, Iram, Tal, Bonanno, Liana, Li, Lulin, Lee, Davis P. +10 more·2019·Nature

Abstract

Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.

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  • Restoration of microglial phagocytosis improves cognitive function in aged mice and promotes a homeostatic microglial transcriptional signature.

    “restoration of microglial phagocytosis improved cognitive function in aged mice and promoted a homeostatic microglial transcriptional signature78.”
  • The 82 genes were strongly enriched for up-regulated genes with immune-modulatory functions, including MHC I-mediated antigen presentation, interferon-response, cell adhesion and complement cascade, as well as regulators of mouse microglia activity including Cd22, Trem2 and Tyrobp.

    “These were strongly enriched for up-regulated genes with immune-modulatory functions (Table S5), including MHC I-mediated antigen presentation, interferon-response, cell adhesion and complement cascade, as well as regulators of mouse microglia activity (Figure 2C) including Cd22 (Pluvinage et al., 2019), Trem2 and Tyrobp (Yeh et al., 2017).”

    From Atlas of the aging mouse brain reveals white matter as vulnerable foci (2023) · cites this paper as Pluvinage et al., 2019

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Authors
Pluvinage, J. V., Haney, M. S., Smith, B. A. H., Sun, J., Iram, T., Bonanno, L., Li, L., Lee, D. P., Morgens, D. W., Yang, A. C., Shuken, S. R., Gate, D., Scott, M., Khatri, P., Luo, J., Bertozzi, C. R., Bassik, M. C., & Wyss-Coray, T.
Affiliations
  • Stanford Medicine (US)
  • VA Palo Alto Health Care System (US)
  • Howard Hughes Medical Institute (US)
Venue
Nature
Published
2019-04
Volume
568
Issue
7751
Pages
187-192
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2934339908
Cited by
459
References
71
Citations by year
2026: 44 · 2025: 73 · 2024: 62 · 2023: 70 · 2022: 71 · 2021: 59 · 2020: 54 · 2019: 26
FWCI
23.14
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (1s10od020141-01)
  • National Institute on Aging (F30AG060638, R01AG045034, DP1AG053015)
  • National Human Genome Research Institute (T32HG000044)
  • National Cancer Institute (R01CA227942)
  • National Institute of General Medical Sciences (T32GM120007, T32GM007365, R01GM059907)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
CD22, microglial phagocytosis, brain aging, microglial homeostasis, sialic acid, myelin debris clearance, amyloid-beta oligomers, alpha-synuclein fibrils, cognitive decline, antibody therapy, CRISPR-Cas9 screen, neurodegeneration
MeSH terms
CRISPR-Associated Protein 9, Aging, Animals, Brain, Cognition, Female, Homeostasis, Male, Mice, Inbred C57BL, Phagocytosis, Sequence Analysis, RNA, Microglia, N-Acetylneuraminic Acid, Mice, Sialic Acid Binding Ig-like Lectin 2, CRISPR-Cas Systems

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