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

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.

SUBMITTER: Wang X

PROVIDER: S-EPMC9393047 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Wang Xu X Liu Mingyue M Zhang Jifeng J Brown Nicholas K NK Zhang Peng P Zhang Yan Y Liu Heng H Du Xuexiang X Wu Wei W Devenport Martin M Tao Weng W Mao-Draayer Yang Y Chen Guo-Yun GY Chen Y Eugene YE Zheng Pan P Liu Yang Y

Cell metabolism 20220801 8

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 s ...[more]

PMID: 35921817

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Project description:Siglec-9, a cell surface transmembrane receptor mainly expressed on B cells, CD56+ NK cells, and CD4+ and CD8+ T cells, is strongly related to the tumor immune microenvironment. However, the expression pattern of Siglec-9 and its prognostic potential have not been investigated in a pan-cancer perspective. This study aimed to explore the association of Siglec-9 with prognosis, tumor stage, molecular subtype, and the immune microenvironment in pan-cancer. The mRNA expression of Siglec-9 was obtained from The Cancer Genome Atlas (TCGA), the Broad Institute Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx). The relationship between Siglec-9 mRNA expression and prognosis was evaluated by the Kaplan-Meier analysis. The correlation between Siglec-9 and tumor-infiltrating immune cells, immune subtype, and molecular subtype was evaluated on Tumor Immune Estimation Resource (TIMER) and Integrated Repository Portal for Tumor-Immune System Interactions (TISIDB). The correlation between Siglec-9 expression and immune checkpoint, mismatch repair (MMR), DNA methyltransferase (DNMT), tumor mutation burden (TMB), and microsatellite instability (MSI) was also analyzed. It showed that Siglec-9 expression was significantly altered in most TCGA tumors. Siglec-9 expression was associated with the prognosis of patients with adrenocortical carcinoma (ACC), lung adenocarcinoma (LUSC), thymoma (THYM), colon adenocarcinoma (COAD), glioblastoma multiforme (GBM), prostate adenocarcinoma (PRAD), esophageal carcinoma (ESCA), and brain lower-grade glioma (LGG). Particularly, increased Siglec-9 expression was strongly correlated with poor prognosis in LGG. Correlation between Siglec-9 expression and tumor stage was also observed in various cancers. In addition, Siglec-9 was positively associated with infiltration of immune cells including neutrophils, dendritic cells (DCs), macrophage, and CD4+ and CD8+ T cells. Moreover, a significant correlation between Siglec-9 and MSI, TMB, MMR, DNMT, immune checkpoint, immune subtype, molecular subtype, and immunomodulators was observed in multiple cancers. Specifically, poor prognostic value and strong correlation to immune cell infiltration were verified with the LGG dataset from the Chinese Glioma Genome Atlas (CGGA). These findings indicated that Siglec-9 can be a novel biomarker and a potential target for cancer immunotherapy.

Dataset Information

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

Publications

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

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