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

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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., Morgens, David W., Yang, Andrew C., Shuken, Steven R., Gate, David, Scott, Madeleine, Khatri, Purvesh, Luo, Jian, Bertozzi, Carolyn R., Bassik, Michael C., Wyss-Coray, Tony·2019·Nature

DOI 10.1038/s41586-019-1088-4PMC PMC6574119

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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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Brawek, B., Skok, M., & Garaschuk, O. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031091 · Cited by 36
“Mechanistically, a recent paper identified the upregulation of CD22 in aged microglia as a negative regulator of phagocytosis [85].”
Background
Physical Activity Rewires the Human Brain against Neurodegeneration
Santiago, J. A., Quinn, J. P., & Potashkin, J. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116223 · Cited by 34
“Strikingly, antibody blockage of CD22 mediated the clearance of amyloid-β oligomers and α-synuclein fibers, and improved cognitive function in mice [32].”
Background
Advanced in vitro models: Microglia in action
Cakir, B., Kiral, F. R., & Park, I.-H. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.004 · Cited by 32
Large‐scale across species transcriptomic analysis identifies genetic selection signatures associated with longevity in mammals
Liu, W., Zhu, P., Li, M., Li, Z., Yu, Y., Liu, G., Du, J., Wang, X., Yang, J., Tian, R., et al. (2023) · The EMBO Journal · doi:10.15252/embj.2022112740 · Cited by 29
Microglia-Centered Combinatorial Strategies Against Glioblastoma
Martins, T. A., Schmassmann, P., Shekarian, T., Boulay, J., Ritz, M., Zanganeh, S., Berg, J. V., & Hütter, G. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.571951 · Cited by 32
Promoters and Antagonists of Phagocytosis: A Plastic and Tunable Response
Freeman, S. A., & Grinstein, S. (2021) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-120219-055903 · Cited by 32
Microglial transcription profiles in mouse and human are driven by APOE4 and sex
Moser, V. A., Workman, M. J., Hurwitz, S. J., Lipman, R. M., Pike, C. J., & Svendsen, C. N. (2021) · iScience · doi:10.1016/j.isci.2021.103238 · Cited by 29
“One of the DAM-APOE genes was recently shown to be a negative regulator of microglial phagocytosis (Pluvinage et al., 2019), suggesting that DAM-APOEs may be defective in this function.”
Background
Advanced therapeutic strategies targeting microglia: beyond neuroinflammation
Kwon, M. (2022) · Archives of Pharmacal Research · doi:10.1007/s12272-022-01406-1 · Cited by 29
Myelin debris phagocytosis in demyelinating disease
Gao, R., Song, S., Tian, M., Wang, L., Zhang, Y., & Li, X. (2024) · Glia · doi:10.1002/glia.24602 · Cited by 31
“CD22 is a signaling molecule that instructs immune cells not to eat certain cells (Pluvinage et al., 2019).”
Antagonism of β-arrestins in IL-4–driven microglia reactivity via the Samd4/mTOR/OXPHOS axis in Parkinson’s disease
Liu, J., Liang, Y., Meng, Q., Chen, J., Ma, J., Zhu, H. Y., Cai, L., Song, N., Ding, J., Fan, Y., et al. (2024) · Science Advances · doi:10.1126/sciadv.adn4845 · Cited by 31
Transcranial Ultrasound Stimulation of Hypothalamus in Aging Mice
Pang, N., Huang, X., Zhou, H., Xia, X., Liu, X., Wang, Y., Meng, W., Bian, T., Meng, L., Xu, L., et al. (2020) · IEEE Transactions on Ultrasonics Ferroelectrics and Frequency Control · doi:10.1109/tuffc.2020.2968479 · Cited by 30
BK Channel-Mediated Microglial Phagocytosis Alleviates Neurological Deficit After Ischemic Stroke
Huang, S., Chen, T., Suo, Q., Shi, R., Khan, H. L., Ma, Y., Tang, Y., Yang, G., & Zhang, Z. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.683769 · Cited by 28
Mechanism of Efferocytosis in Determining Ischaemic Stroke Resolution—Diving into Microglia/Macrophage Functions and Therapeutic Modality
Xie, X.-D., Dong, S., Liu, R., Shi, L., & Zhu, T. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04060-4 · Cited by 28
“In addition to CD300A, CD22 expressed on aged microglia is regarded as another negative regulator of phagocytosis [92].”
From mechanism to therapy: the journey of CD24 in cancer
Zhao, K., Wu, C., Li, X., Niu, M., Wu, D., Cui, X., & Hai, Z. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1401528 · Cited by 28
Glycoengineering artificial receptors for microglia to phagocytose Aβ aggregates
Yu, D., Liu, C., Zhang, H., Ren, J., & Qu, X. (2021) · Chemical Science · doi:10.1039/d0sc07067j · Cited by 28
Siglec-9 is an inhibitory receptor on human mast cells in vitro
Miralda, I., Samanas, N. B., Seo, A. J., Foronda, J. S., Sachen, J., Hui, Y. Y., Morrison, S. D., Oskeritzian, C. A., & Piliponsky, A. M. (2023) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2023.04.007 · Cited by 29
Unique molecular signature in mucolipidosis type IV microglia
Cougnoux, A., Drummond, R. A., Fellmeth, M., Navid, F., Collar, A. L., Iben, J., Kulkarni, A. B., Pickel, J. M., Schiffmann, R., Wassif, C. A., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1672-4 · Cited by 29
Metabolic regulation of immune cells in proinflammatory microenvironments and diseases during ageing
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Identification of cerebral spinal fluid protein biomarkers in Niemann-Pick disease, type C1
Campbell, K. S., Cawley, N. X., Luke, R., Scott, K. E. J., Johnson, N., Farhat, N. Y., Alexander, D. M., Wassif, C. A., Li, W., Cologna, S. M., et al. (2023) · Biomarker Research · doi:10.1186/s40364-023-00448-x · Cited by 26
“We have previously shown that CD22, a modulator of microglial function [38], is increased in CSF from individuals with NPC1 [14].”
Background
How the gut microbiota impacts neurodegenerative diseases by modulating CNS immune cells
Schaible, P., Henschel, J., & Erny, D. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03371-0 · Cited by 32
“Thereby, the uptake of myelin debris, amyloid-β oligomers and α-synuclein fibrils could be increased, subsequently improving cognitive function [128].”
sTREM-1 promotes the phagocytic function of microglia to induce hippocampus damage via the PI3K–AKT signaling pathway
Lü, L., Liu, X., Fu, J., Liang, J., Hou, Y., & Dou, H. (2022) · Scientific Reports · doi:10.1038/s41598-022-10973-8 · Cited by 26
Microglia Mediate Contact-Independent Neuronal Network Remodeling via Secreted Neuraminidase-3 Associated with Extracellular Vesicles
Delaveris, C. S., Wang, C. L., Riley, N. M., Li, S., Kulkarni, R. U., & Bertozzi, C. R. (2023) · ACS Central Science · doi:10.1021/acscentsci.3c01066 · Cited by 25
Self-citation
Transcriptional and epigenetic regulation of microglia in maintenance of brain homeostasis and neurodegeneration
Maurya, S. K., Gupta, S., & Mishra, R. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1072046 · Cited by 26
Microglia and macrophages in the neuro-glia-vascular unit: From identity to functions
Chen, S., Li, J., Meng, S., He, T., Shi, Z., Wang, C., Wang, Y., Cao, H., Huang, Y., Zhang, Y., et al. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106066 · Cited by 24
“In previous studies, they have been observed to phagocytose neurons[60], glioma cells [61], dead cell debris [62], dendritic spines[63; 64], extracellular matrix, and invading pathogens[60].”
Siglecs as modulators of macrophage phenotype and function
Kukan, E. N., Fabiano, G. L., & Cobb, B. A. (2024) · Seminars in Immunology · doi:10.1016/j.smim.2024.101887 · Cited by 24
Progressive long‐term spatial memory loss following repeat concussive and subconcussive brain injury in mice, associated with dorsal hippocampal neuron loss, microglial phenotype shift, and vascular abnormalities
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“The loss of trophic support, together with the diminished ability to maintain homeostasis (Dubbelaar et al., 2018; Pluvinage et al., 2019), would then be the likely consequences of the decreased microglial abundance we found for dorsal hippocampus in the repeat subconcussive mice.”
Background
The Endogenous Metabolite Glycerophosphocholine Promotes Longevity and Fitness in Caenorhabditis elegans
Liu, J., Zheng, R.-Q., Wang, Y., Liu, Y., Jiang, S., Wang, X., He, K., Pan, X., Zhou, T., Li, T., et al. (2022) · Metabolites · doi:10.3390/metabo12020177 · Cited by 24
“Tony Wyss-Coray’s group identified several factors that affected brain aging and cognitive fun tio in the mouse model, incl ding a cano ical B cell receptor, CD22 [29], the MHC molecul β2-microglobulin (B2M) [30] and so on.”
BackgroundInfluential
The Emerging Role of Extracellular Vesicle Derived From Neurons/Neurogliocytes in Central Nervous System Diseases: Novel Insights Into Ischemic Stroke
Li, F., Kang, X., Xin, W., & Li, X. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.890698 · Cited by 25
Ensheathing glia promote increased lifespan and healthy brain aging
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Novel pathophysiological insights into CAR-T cell associated neurotoxicity
Genoud, V., & Migliorini, D. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1108297 · Cited by 28
“A single-cell RNA sequencing study confirmed the expression of CD22 in microglia cells (75), which exerts negative regulation of microglia phagocytosis (79).”
Background
Biological agents and the aging brain: glial inflammation and neurotoxic signaling
Latham, A. S., Moreno, J. A., & Geer, C. E. (2023) · Frontiers in Aging · doi:10.3389/fragi.2023.1244149 · Cited by 27
Suppressor mutations in Mecp2 -null mice implicate the DNA damage response in Rett syndrome pathologyPreprint
Enikanolaiye, A., Ruston, J., Zeng, R., Taylor, C., Schrock, M., Buchovecky, C. M., Shendure, J., Acar, E. F., & Justice, M. J. (2020) · Genome Research · doi:10.1101/gr.258400.119 · Cited by 25
“CD22 antigen (Cd22) is a canonical B-cell receptor that clusters in synaptic function because mutations in Cd22 increase the ability of microglia to clear myelin debris and remodel dendrites (Pluvinage et al. 2019).”
Background
Microglia-derived nanovesicles synchronize macroautophagy and chaperone-mediated autophagy for Alzheimer’s disease therapy
Li, M., Chen, S., Guo, R., Wang, Y., Yang, M., Liu, Y., Zhang, Q., Zhu, S., Li, J., Chen, F., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02453-y · Cited by 24
“31 To determine whether AR@ENV upregulates autophagy, we performed western blot analysis to assess autophagy-related protein expression in HT22 neurons treated with different nanovesicles (Fig.”
Microglia in Alzheimer’s Disease
Süß, P., & Schlachetzki, J. C. M. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200212155234 · Cited by 26
p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function
Perea, J. R., Bolós, M., Cuadros, R., García, E., García‐Escudero, V., Hernández, F., McManus, R. M., Heneka, M. T., & Ávila, J. (2022) · Molecular Neurobiology · doi:10.1007/s12035-021-02715-0 · Cited by 24
Role of Microglia in Psychostimulant Addiction
da Silva, M. C. M., Iglesias, L. P., Candelario‐Jalil, E., Khoshbouei, H., Moreira, F. A., & de Oliveira, A. C. P. (2022) · Current Neuropharmacology · doi:10.2174/1570159x21666221208142151 · Cited by 26
“Upregulation of CD22 pathway is related to impaired microglia phagocytic activity and surveillance, as well as cognitive impairment in aged mice [72, 74].”
Microglia rely on SYK signalling to mount neuroprotective responses in models of Alzheimer's disease and multiple sclerosis
Ennerfelt, H. E., & Lukens, J. R. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1178 · Cited by 22
α-Synuclein pathology from the body to the brain: so many seeds so close to the central soil
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“…they are more prone to undergo neuron–neuron, glia– neuron, and peripheral cell-brain cell propagation, forming the spreading mechanism of pathological α-Syn among the central nervous system and from the peripheral tissues to the central nervous system (Pluvinage et al., 2019; Yuan et al., 2022).”
Background
Microglia orchestrate synaptic and neuronal stripping: Implication in neuropsychiatric lupus
Zhou, Y., Chen, L., Zheng, X., Fang, Q., Qian, Y., Xu, T., Liang, J., Zhang, H., Han, X., & Sun, L. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.18190 · Cited by 23
“26,39,50 In this study, we found that compared with control mice, MRL/lpr mice showed decreased dendritic spine density and increased expression of synaptic markers, such as PSD95, within microglia.”
Result
Therapeutic potential to target sialylation and SIGLECs in neurodegenerative and psychiatric diseases
Wißfeld, J., Assale, T. A., Cuevas-Ríos, G., Liao, H., & Neumann, H. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1330874 · Cited by 23
“Long-term SIGLEC-2 blockade restored microglial homeostasis and ultimately improved the cognitive function in aged mice (121).”
Background
Associations of plasma soluble CD22 levels with brain amyloid burden and cognitive decline in Alzheimer’s disease
Bu, X., Sun, P., Fan, D., Wang, J., Sun, H., Cheng, Y., Zeng, G., Chen, D., Li, H., Yi, X., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm5667 · Cited by 23
“It was found that CD22 is a negative regulator of microglial phagocytosis in the brain, and that inhibition of CD22 promotes microglial phagocytosis of A  oligomers and lessens cognitive impairment in aged mice ( 10 ).”
BackgroundInfluential

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: Pluvinage, John V.
Haney, Michael S.
Smith, Benjamin A. H.
Sun, Jerry
Iram, Tal
Li, Lulin
Morgens, David W.
Yang, Andrew C.
Shuken, Steven R.
Gate, David
Scott, Madeleine
Khatri, Purvesh
Luo, Jian
Bertozzi, Carolyn R.
Bassik, Michael C.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2019-04
Volume: 568
Issue: 7751
Pages: 187-192
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-019-1088-4
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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CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

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