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CD22 blockade restores homeostatic microglial phagocytosis in ageing brains
Open accessAbstract
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 improved cognitive function in aged mice and promoted a homeostatic microglial transcriptional signature78.”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [78]
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“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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BackgroundPhagocytic astrocytes: Emerging from the shadows of microglia
Konishi, H., Koizumi, S., & Kiyama, H. (2022) · Glia · doi:10.1002/glia.24145 · Cited by 88
Targeting immunosenescence and inflammaging: advancing longevity research
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“Additionally, CD22 antibody blockade, targeting a negative regulator of microglial phagocytosis, restores immune cell function and cognitive performance in aged mice, highlighting its potential for immune rejuvenation 85 – 87 .”
Noteworthy perspectives on microglia in neuropsychiatric disorders
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“These receptors act at different levels, including recognition, target biding, and phagosome formation [29, 134–141].”
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“In mammals, glia composition and properties display developmental and age-related dynamics (44, 55, 56) including a shift to a more neuroprotective function as the brain ages (57), and restoration of the phagocytic function of microglia in aged mice improves their cognitive performance (58).”
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Peripheral and central neuroimmune mechanisms in Alzheimer’s disease pathogenesis
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“Studies have demonstrated that CD22 functions as a negative regulator of microglial phagocytosis and is upregulated in aged microglia [123].”
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“CD22 was identified as a negative regulator of microglial phagocytosis in the aging brain [40] and was found to be upregulated in microglia in mouse models of AD [41].”
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Central Nervous System Remyelination: Roles of Glia and Innate Immune Cells
Baaklini, C. S., Rawji, K. S., Duncan, G. J., Ho, M. F. S., & Plemel, J. R. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00225 · Cited by 88
Microglia transcriptional states and their functional significance: Context drives diversity
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Biomaterials in treatment of Alzheimer's disease
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Microglia and Wnt Pathways: Prospects for Inflammation in Alzheimer’s Disease
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“CD22, a negative regulator of microglial phagocytosis, is elevated in plasma from AD patients as soluble CD22 [96].”
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“…isotype + vehicle, ####p .0001 versus isotype + ST-Inh, &&&&p .0001 versus isotype + sialidase [Color figure can be viewed at wileyonlinelibrary.com] (Pluvinage et al., 2019) found that desialylation of BV-2 cells stim- ulated phagocytosis of beads, and this was attributed to Siglec-2 (sialic…”
BackgroundA novel Tmem119-tdTomato reporter mouse model for studying microglia in the central nervous system
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“In addition, α2,6-linked sialic acid but not α2,3-linked sialic acid is involved in CD22-mediated inhibition of microglial phagocytosis (Pluvinage et al., 2019).”
BackgroundGonzalez-Gil, A., Porell, R. N., Fernandes, S. M., Maenpaa, E., Li, T. A., Li, T., Wong, P. C., Aoki, K., Tiemeyer, M., Yu, Z. J., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101960 · Cited by 71
Neuroimmune cleanup crews in brain injury
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Targeted glycan degradation potentiates cellular immunotherapy for solid tumors
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Modulation of immune cell reactivity with cis -binding Siglec agonists
Delaveris, C. S., Chiu, S. H., Riley, N. M., & Bertozzi, C. R. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2012408118 · Cited by 70
Self-citationSialylation acts as a checkpoint for innate immune responses in the central nervous system
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Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection
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“Although CD300a is the only PS receptor known to be involved in the suppression of efferocytosis, the canonical B cell receptor CD22 has been reported as a negative regulator of phagocytosis in microglia (43).”
BackgroundShuken, S. R., Rutledge, J., Iram, T., Losada, P. M., Wilson, E. N., Andreasson, K. I., Leib, R. D., & Wyss‐Coray, T. (2022) · Nature Aging · doi:10.1038/s43587-022-00196-x · Cited by 64
Self-citationHow the immune system shapes neurodegenerative diseases
Mason, H. D., & McGavern, D. B. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.08.001 · Cited by 67
Sialometabolism in Brain Health and Alzheimer’s Disease
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Metadata
- 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)
- ORCID
- Venue
- Nature
- Published
- 2019-04
- Volume
- 568
- Issue
- 7751
- Pages
- 187-192
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6574119
- 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
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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