美国耶鲁大学医学院Vishwa Deep Dixit团队近期取得重要工作进展，他们研究发现基质细胞蛋白SPARC在衰老过程中诱导巨噬细胞中的炎症干扰素应答反应。该项研究成果2022年8月12日在线发表于《免疫》杂志上。

研究人员发现基质细胞蛋白，富含半胱氨酸的酸性分泌性蛋白（SPARC），在人类持续2年14% 的CR中受到抑制，并因肥胖而升高。SPARC将抗炎巨噬细胞转化为促炎表型，通过转录因子IRF3/7诱导干扰素刺激基因（ISG）表达。从机制上讲，SPARC诱导的ISG依赖于toll样受体4（TLR4）介导的TBK1、IRF3、IFN-β 和STAT1信号传导，而不参与Myd88通路。在代谢方面，SPARC可抑制巨噬细胞线粒体呼吸，抑制糖酵解可消除SPARC诱导的ISG。

此外，SPARC的N端酸性结构域是ISG诱导所必需的，而脂肪细胞特异性缺失SPARC可减少炎症并延长衰老过程中的健康跨度。总的来说，SPARC是一种CR模拟脂肪因子，是炎症和干扰素反应的免疫代谢检查点，可用于延缓与年龄相关的代谢和功能衰退。

据介绍，热量限制(CR)诱导的免疫代谢适应降低了衰老引起的慢性疾病的风险。

附：英文原文

Title: The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging

Author: Seungjin Ryu, Sviatoslav Sidorov, Eric Ravussin, Maxim Artyomov, Akiko Iwasaki, Andrew Wang, Vishwa Deep Dixit

Issue&Volume: 2022-08-12

Abstract: The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), was inhibited by 2 years of 14% sustained CR in humans and elevated by obesity. SPARC converted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon-stimulated gene (ISG) expression via the transcription factors IRF3/7. Mechanistically, SPARC-induced ISGs were dependent on toll-like receptor-4 (TLR4)-mediated TBK1, IRF3, IFN-β, and STAT1 signaling without engaging the Myd88 pathway. Metabolically, SPARC dampened mitochondrial respiration, and inhibition of glycolysis abrogated ISG induction by SPARC in macrophages. Furthermore, the N-terminal acidic domain of SPARC was required for ISG induction, while adipocyte-specific deletion of SPARC reduced inflammation and extended health span during aging. Collectively, SPARC, a CR-mimetic adipokine, is an immunometabolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline.

DOI: 10.1016/j.immuni.2022.07.007

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00340-5