Oxidative Stress-Induced Microglial CD22 Upregulation Impairs Phagocytosis and Exacerbates Huntingtons Disease

Lee, Y. H.; Siew, J. J.; Lee, C.-W.; Chen, H.-M.; Lu, Y.-T.; Sridharan, D.; Huang, P.-C. J.; Chang, H.-C.; Guu, S.-Y.; Wang, P.-Y.; Wang, Y.-F.; Liang, S.-Y.; Khoo, K.-H.; Angata, T.; Chern, Y.

doi:10.64898/2026.03.11.710967

bioRxiv · 10.64898/2026.03.11.710967

Oxidative Stress-Induced Microglial CD22 Upregulation Impairs Phagocytosis and Exacerbates Huntingtons Disease

Lee, Y. H.·Siew, J. J.·Lee, C.-W.·Chen, H.-M.·Lu, Y.-T.·Sridharan, D.·Huang, P.-C. J.·Chang, H.-C.·Guu, S.-Y.·Wang, P.-Y.·Wang, Y.-F.·Liang, S.-Y.·Khoo, K.-H.·Angata, T.·Chern, Y.

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Abstract

BackgroundHuntingtons disease (HD) is a neurodegenerative disorder caused by an abnormal polyglutamine expansion in mutant huntingtin (mHTT) and is characterized by movement dysfunction and neuronal loss. Siglecs, a family of sialic acid-binding proteins, are expressed on brain microglia and implicated in Alzheimers disease. Sialic acids are abundant in mammalian brains and cap the termini of the glycocalyx of various brain cells. Alterations in sialoglycans or Siglecs may affect interactions between microglia and other brain cells. However, the roles of Siglecs in HD have not been investigated. MethodsWe profiled Siglecs in postmortem caudate nucleus samples from HD subjects and in a mouse model of HD (R6/2) using RT-qPCR and mass cytometry analyses. CD22 functions in microglia were evaluated using a microglial cell line (BV2) and primary microglia. Native ligands for microglial CD22 were assessed via glycomic profiling and flow cytometry. Regulation of CD22 ligands in astrocytes was investigated in an astrocytic cell line (C8-D1A) and primary astrocytes. The role of CD22 in HD was examined by genetic deletion in HD mice, followed by behavioral analyses and pathological evaluation with immunofluorescence staining and MRI. ResultsUpregulation of CD22 in microglia, observed in the brains of patients and mice with HD, impairs microglial phagocytosis via ITIM-ITAM signaling crosstalk. This CD22 upregulation was driven by chronic oxidative stress, as antioxidant treatment (N-acetylcysteine) markedly normalized CD22 levels. CD22 ligand, 2,6-sialylated-6-sulfo-LacNAc, primarily expressed by astrocytes, was significantly reduced in HD mice. mHTT, but not wild-type HTT, suppressed ligand synthesis in astrocytes under elevated oxidative stress, allowing more CD22 on the microglial surface to inhibit phagocytosis. Treatment with a neutralizing antibody or ligand-enriched extracellular vesicles depleted surface CD22 and restored the phagocytic function of microglia. Genetic deletion of CD22 in HD mice improved rotarod performance, reduced mHTT inclusion burden, increased Darpp32 expression, and alleviated brain atrophy, supporting the concept that CD22-mediated inhibition of microglial phagocytosis contributes to HD pathogenesis. ConclusionOur findings suggest that CD22 acts as a checkpoint-like regulator that restrains microglial phagocytosis and contributes to HD progression when astrocyte-microglia communication is impaired, thereby highlighting CD22 as a promising therapeutic target.

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Lee, Y. H., Siew, J. J., Lee, C.-W., Chen, H.-M., Lu, Y.-T., Sridharan, D., Huang, P.-C. J., Chang, H.-C., Guu, S.-Y., Wang, P.-Y., Wang, Y.-F., Liang, S.-Y., Khoo, K.-H., Angata, T., Chern, Y.. 2026-03-13. Oxidative Stress-Induced Microglial CD22 Upregulation Impairs Phagocytosis and Exacerbates Huntingtons Disease. https://doi.org/10.64898/2026.03.11.710967

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