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.

调节代谢疾病背后的慢性炎症的分子相互作用仍然很大程度上未知。由于 CD24-Siglec 相互作用调节对危险相关分子模式 (DAMP) 的炎症反应，我们培育了多个具有Cd24或Siglec基因单一或组合突变的小鼠品系，以探索 CD24-Siglec 相互作用在炎症和代谢紊乱中的作用。在这里，我们报告 CD24-Siglec-E 轴（而不是其他 Siglec）是肥胖相关代谢功能障碍的关键抑制因子。CD24-Siglec-E 通路失活会加剧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)，而 CD24Fc 治疗则可缓解。从机制上讲，Siglec-E 对 CD24 的唾液酸化依赖性识别会诱导 SHP-1 募集并抑制代谢炎症，从而预防代谢综合征。CD24Fc (NCT02650895) 的首次人体研究支持了该途径在人类脂质代谢和炎症中的重要性。这些发现将 CD24-Siglec-E 轴确定为针对代谢炎症和代谢紊乱的先天免疫检查点，并提出了代谢疾病的有希望的治疗靶点。