CD24-Siglec axis is an innate immune checkpoint against metaflammation and metabolic disorder.
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Author
Wang, XuLiu, Mingyue
Zhang, Jifeng
Brown, Nicholas K
Zhang, Peng
Zhang, Yan
Liu, Heng
Du, Xuexiang
Wu, Wei
Devenport, Martin
Tao, Weng
Mao-Draayer, Yang
Chen, Guo-Yun
Chen, Y Eugene
Zheng, Pan
Liu, Yang
Date
2022-08-02Journal
Cell MetabolismPublisher
ElsevierType
Article
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The molecular interactions that regulate chronic inflammation underlying metabolic disease remain largely unknown. Since the CD24-Siglec interaction regulates inflammatory response to danger-associated molecular patterns (DAMPs), we have generated multiple mouse strains with single or combined mutations of Cd24 or Siglec genes to explore the role of the CD24-Siglec interaction in metaflammation and metabolic disorder. Here, we report that the CD24-Siglec-E axis, but not other Siglecs, is a key suppressor of obesity-related metabolic dysfunction. Inactivation of the CD24-Siglec-E pathway exacerbates, while CD24Fc treatment alleviates, diet-induced metabolic disorders, including obesity, dyslipidemia, insulin resistance, and nonalcoholic steatohepatitis (NASH). Mechanistically, sialylation-dependent recognition of CD24 by Siglec-E induces SHP-1 recruitment and represses metaflammation to protect against metabolic syndrome. A first-in-human study of CD24Fc (NCT02650895) supports the significance of this pathway in human lipid metabolism and inflammation. These findings identify the CD24-Siglec-E axis as an innate immune checkpoint against metaflammation and metabolic disorder and suggest a promising therapeutic target for metabolic disease.Rights/Terms
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.Keyword
CD24NASH
Siglec-E
Siglecs
insulin resistance
metabolic syndrome
metaflammation
obesity
sialic acid-binding immunoglobulin-like lectins
sialylation
Identifier to cite or link to this item
http://hdl.handle.net/10713/19547ae974a485f413a2113503eed53cd6c53
10.1016/j.cmet.2022.07.005
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