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

Immunity. 2022 Sep 13;55(9):1609-1626.e7. doi: 10.1016/j.immuni.2022.07.007. Epub 2022 Aug 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.

Keywords: SPARC; TLR4; caloric restriction; inflammation; interferon-stimulated gene; macrophage; matricellular protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Humans
  • Inflammation / metabolism
  • Interferons* / metabolism
  • Macrophages* / metabolism
  • Osteonectin* / genetics
  • Osteonectin* / metabolism

Substances

  • Osteonectin
  • SPARC protein, human
  • Interferons