Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
Immunity. 2022 Sep 13;55(9):1609-1626.e7. doi: 10.1016/j.immuni.2022.07.007. Epub 2022 Aug 12.
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.
衰老大龄相关慢性疾病风险可以通过热量限制（CR）诱导的免疫代谢适应来降低。在这里，我们发现细胞外基质蛋白富含半胱氨酸酸性分泌蛋白（SPARC）在人类中被 14%持续 2 年的 CR 抑制，在肥胖中被上调。SPARC 通过转录因子 IRF3/7 将抗炎巨噬细胞转化为促炎表型，并诱导干扰素刺激基因（ISG）表达。在机制上，SPARC 诱导的 ISGs 依赖于 Toll 样受体 4（TLR4）介导的 TBK1、IRF3、IFN-β 和 STAT1 信号传导，而不涉及 Myd88 途径。在代谢上，SPARC 抑制线粒体呼吸，而抑制糖酵解则可以消除 SPARC 在巨噬细胞中诱导 ISG 的作用。此外，SPARC 的 N 端酸性结构域对于 ISG 的诱导是必需的，而脂肪细胞特异性缺失 SPARC 可以减少炎症并延长衰老过程中的健康寿命。总之，作为一种 CR 模拟脂肪因子，SPARC 是炎症和干扰素反应的免疫代谢检查点，可能成为延缓与年龄相关的代谢和功能下降的靶点。
