The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging.
The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging.
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DOI：
10.1016/j.immuni.2022.07.007
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发表时间：
2022-09-13
期刊：
影响因子：
32.4
通讯作者：
Dixit, Vishwa Deep
中科院分区：
文献类型：
--
作者：
Ryu, Seungjin;Sidorov, Sviatoslav;Ravussin, Eric;Artyomov, Maxim;Iwasaki, Akiko;Wang, Andrew;Dixit, Vishwa Deep
卡路里限制(CR)诱导的免疫代谢适应降低了由衰老引起的慢性病的风险。在这里，我们发现基质细胞蛋白，酸性和富含半胱氨酸的分泌蛋白(SPARC)在人类持续两年的CR中被抑制，并因肥胖而升高。SPARC通过转录因子IRF3/7诱导干扰素刺激基因(ISG)的表达，将抗炎巨噬细胞转化为促炎表型。机制上，SPARC诱导的ISG依赖于Toll样受体4(Toll-like Receptor-4，TLR4)介导的Toll样受体-4(Toll-like Receptor-4，IRF3)、干扰素-β和STAT1信号，而不涉及MyD88途径。代谢方面，SPARC抑制线粒体呼吸，抑制糖酵解可阻断SPARC对巨噬细胞ISG的诱导。此外，SPARC的N末端酸性结构域是诱导ISG所必需的，而脂肪细胞特异性的SPARC缺失可以减少炎症，延长衰老期间的健康寿命。总体而言，SPARC是一种类似CR的脂肪因子，是炎症和干扰素反应的免疫代谢检查点，可能以延缓与年龄相关的代谢和功能衰退为目标。卡路里限制(CR)可减少炎症并延长寿命，但CR模拟物改善健康寿命的身份尚不清楚。Ryu等人揭示，在人类中持续的CR可以减少脂肪SPARC。脂肪细胞中SPARC的升高促进干扰素反应和炎症，而脂肪细胞中SPARC的减少则保护衰老相关的炎症和代谢功能障碍。
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 two-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 healthspan 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. Caloric restriction (CR) reduces inflammation and enhances longevity but the identity of CR-mimetics that improve healthspan is unclear. Ryu et al reveal that sustained CR in humans reduces adipose SPARC. Elevation of SPARC promotes interferon-response and inflammation while reduction of SPARC in adipocytes protects against aging-related inflammation and metabolic dysfunction.
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