CD24-Siglec axis is an innate immune checkpoint against metaflammation and metabolic disorder

Xu Wang; Mingyue Liu; Jifeng Zhang; Nicholas K Brown; Peng Zhang; Yan Zhang; Heng Liu; Xuexiang Du; Wei Wu; Martin Devenport; Weng Tao; Yang Mao-Draayer; Guo-Yun Chen; Y Eugene Chen; Pan Zheng; Yang Liu

doi:10.1016/j.cmet.2022.07.005

CD24-Siglec axis is an innate immune checkpoint against metaflammation and metabolic disorder

Cell Metab. 2022 Aug 2;34(8):1088-1103.e6. doi: 10.1016/j.cmet.2022.07.005.

Authors

Xu Wang¹, Mingyue Liu¹, Jifeng Zhang², Nicholas K Brown³, Peng Zhang⁴, Yan Zhang⁵, Heng Liu¹, Xuexiang Du⁶, Wei Wu⁷, Martin Devenport⁸, Weng Tao⁸, Yang Mao-Draayer⁹, Guo-Yun Chen¹⁰, Y Eugene Chen², Pan Zheng¹¹, Yang Liu¹²

Affiliations

¹ Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
² Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48105, USA.
³ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
⁵ Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁶ Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
⁷ Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; OncoImmune, Inc., Rockville, MD 20850, USA; OncoC4, Inc., Rockville, MD 20850, USA.
⁸ OncoImmune, Inc., Rockville, MD 20850, USA; OncoC4, Inc., Rockville, MD 20850, USA.
⁹ Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48105, USA.
¹⁰ Children's Foundation Research Institute, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
¹¹ Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; OncoImmune, Inc., Rockville, MD 20850, USA; OncoC4, Inc., Rockville, MD 20850, USA. Electronic address: pzheng@oncoc4.com.
¹² Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; OncoImmune, Inc., Rockville, MD 20850, USA; OncoC4, Inc., Rockville, MD 20850, USA. Electronic address: yangl@oncoc4.com.

Abstract

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.

Keywords: CD24; NASH; Siglec-E; Siglecs; insulin resistance; metabolic syndrome; metaflammation; obesity; sialic acid-binding immunoglobulin-like lectins; sialylation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD24 Antigen / genetics
CD24 Antigen / metabolism
Clinical Studies as Topic
Humans
Inflammation
Metabolic Diseases*
Mice
Obesity
Phagocytosis
Sialic Acid Binding Immunoglobulin-like Lectins* / metabolism

CD24-Siglec axis is an innate immune checkpoint against metaflammation and metabolic disorder

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