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

The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometa-bolic 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 con-verted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon -stim-ulated 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-b, 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 immunometa-bolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline.

Automated summary

Caloric restriction reduces the risk of chronic diseases caused by aging. The matricellular protein SPARC converts anti-inflammatory macrophages into pro-inflammatory cells and induces interferon-stimulated gene expression. Furthermore, SPARC inhibits mitochondrial respiration and is involved in immunometabolic regulation.