Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48105, USA.
Cell Metab. 2022 Aug 2;34(8):1088-1103.e6. doi: 10.1016/j.cmet.2022.07.005.
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.
调控代谢性疾病慢性炎症的分子相互作用在很大程度上仍然未知。由于 CD24-Siglec 相互作用调节了对危险相关分子模式（DAMPs）的炎症反应，我们已经生成了多种具有单个或组合的 Cd24 或 Siglec 基因突变的小鼠品系，以探索 CD24-Siglec 相互作用在代谢性炎症和代谢紊乱中的作用。在这里，我们报告 CD24-Siglec-E 轴，但不是其他 Siglecs，是肥胖相关代谢功能障碍的关键抑制因子。CD24-Siglec-E 通路的失活会加剧，而 CD24Fc 处理则会减轻饮食引起的代谢紊乱，包括肥胖、血脂异常、胰岛素抵抗和非酒精性脂肪性肝炎（NASH）。在机制上，Siglec-E 对 CD24 的唾液酸化依赖性识别诱导 SHP-1 募集并抑制代谢性炎症，从而防止代谢综合征。CD24Fc（NCT02650895）的首次人体研究支持该途径在人类脂质代谢和炎症中的重要性。这些发现确定了 CD24-Siglec-E 轴作为针对代谢性炎症和代谢紊乱的固有免疫检查点，并为代谢性疾病提供了一个有前途的治疗靶点。
