CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

John V. Pluvinage; Michael S. Haney; Benjamin A.H. Smith; Jerry Sun; Tal Iram; Liana Bonanno; Lulin Li; Davis P. Lee; David W. Morgens; Andrew C. Yang; Steven R. Shuken; David Gate; Madeleine Scott; Purvesh Khatri; Jian Luo; Carolyn R. Bertozzi; Michael C. Bassik; Tony Wyss-Coray

doi:10.1038/s41586-019-1088-4

CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

John V. Pluvinage, Michael S. Haney, Benjamin A.H. Smith, Jerry Sun, Tal Iram, Liana Bonanno, Lulin Li, Davis P. Lee, David W. Morgens, Andrew C. Yang, Steven R. Shuken, David Gate, Madeleine Scott, Purvesh Khatri, Jian Luo, Carolyn R. Bertozzi, Michael C. Bassik, Tony Wyss-Coray^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

305 Scopus citations

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.

Original language	English (US)
Pages (from-to)	187-192
Number of pages	6
Journal	Nature
Volume	568
Issue number	7751
DOIs	https://doi.org/10.1038/s41586-019-1088-4
State	Published - Apr 11 2019

Funding

Acknowledgements We thank the members of the Wyss-Coray, Bassik and Bertozzi laboratories for feedback and support; M. Macauley, Q. Li and S. Nagaraja for helpful discussions, M. Bennett and F.C. Bennett for critical reading of the manuscript, H. Zhang and K. Dickey for laboratory management, R. Ballet, E. Butcher, J. Paulson and L. Nitscke for Cd22−/− mice, B. Lehallier for RNA-seq analysis scripts, L. Zhou for RNAscope advice, J. Hudak for reagents, H. Yousef for histology protocols and C. Cain for flow cytometry technical expertise. This work was funded by the Department of Veterans Affairs (T.W.-C.), the National Institute on Aging (R01-AG045034 and DP1-AG053015 to T.W.-C., F30AG060638 to J.V.P.), the National Institute of General Medical Sciences (R01-GM059907 to C.R.B.), the NOMIS Foundation (T.W.-C.), The Glenn Foundation for Aging Research (T.W.-C.), the Stanford University Medical Scientist Training Program (T32GM007365, J.V.P., B.A.H.S., L.B. and M.S.), the Big Idea Brain Rejuvenation Project from the Wu Tsai Neurosciences Institute (T.W.-C., M.C.B. and C.R.B.) and Cure Alzheimer’s Fund (T.W.-C.). This work used the Stanford Center for Genomics and Personalized Medicine (NIH S10OD020141).

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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. (2019). CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature, 568(7751), 187-192. https://doi.org/10.1038/s41586-019-1088-4

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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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N2 - 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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CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

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