St3gal5-mediated sialylation of glyco-CD177 on neutrophils restricts neuroinflammation following CNS injury
Abstract
Neutrophils are the most abundant circulating leukocyte population that play critical roles in neuroinflammation following central nervous system (CNS) injury. CD177, a glycoprotein on neutrophils, is emerging as an important immune regulator which can fundamentally affect multiple human inflammatory diseases. However, the role and regulatory mechanism of CD177 glycobiology of neutrophils in neuroinflammation remain elusive. Here, we show that CD177 + neutrophils expand significantly and infiltrate the injured brain following CNS injury both in the human and mouse. Using single-cell RNA sequencing and genetic approaches, we find CD177 + neutrophils as an anti-inflammatory subset that is critical for modulating neuroinflammation after CNS injury. We further identify St3gal5, a sialyltransferase (ST), that can mediate the sialylation and cell surface presentation of glyco-CD177 on neutrophils. Glycoproteomics reveal downregulated sialylation levels in St3gal5-deficient neutrophils. Neutrophil-specific depletion of St3gal5 prevents the cell surface presentation of CD177 on brain-infiltrated neutrophils and exacerbates neuroinflammation. Administration of the FDA-approved anticonvulsant valproic acid (VPA), an St3gal5 upregulator, promotes the glycosylation of neutrophils and attenuates neuroinflammation following CNS injury. Our study reveals a glycoimmuno-regulatory effect of neutrophils and suggests VPA as a neutrophil glycobiology targeting approach to combat neuroinflammation following CNS injury.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Tingting Huang
Shanghai Key Laboratory of Atmospheric Particle Pollution and Prevention, National Observations and Research Station for Wetland Ecosystems of the Yangtze Estuary, IRDR International Center of Excellence on Risk Interconnectivity and Governance on Weather, Department of Environmental Science & Engineering
Wanqing Xie
Yunlu Guo
Department of Anesthesiology, Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Yan Li
Jiemin Yin
Department of Anesthesiology, Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Xia Jin
Department of Anesthesiology, Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Yezhi Ma
Department of Anesthesiology, Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Yueman Zhang
Department of Anesthesiology, Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Dan Huang
School of Chemistry and Chemical Engineering, State Key Laboratory of Luminescent Materials and Devices
Caiyang Chen
Department of Anesthesiology, Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Xin Wang
Ziyu Zhu
Department of Anesthesiology, Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Yu Gan
Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Arthur Liesz
Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität München
Weifeng Yu
Department of Anesthesiology, Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine
Junying Yuan
Peiying Li
Department of Anesthesiology, Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine