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

Seungjin Ryu1, Sviatoslav Sidorov2, Eric Ravussin3

  • 1Department 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.

Immunity
|August 13, 2022
PubMed

Insights

Caloric restriction (CR) inhibits SPARC, a protein that promotes inflammation and interferon responses in aging. Targeting SPARC may delay age-related decline by modulating immunometabolic adaptation.

Area of Science:

  • Immunometabolism
  • Aging Research
  • Molecular Biology

Background:

  • Caloric restriction (CR) mitigates age-related chronic diseases via immunometabolic adaptation.
  • The matricellular protein SPARC is implicated in inflammation and metabolic processes.

Purpose of the Study:

  • To investigate the role of SPARC in CR-induced immunometabolic adaptation and its impact on aging.
  • To elucidate the molecular mechanisms by which SPARC influences macrophage phenotype and interferon response.

Main Methods:

  • Human study involving 2 years of sustained 14% CR.
  • In vitro studies using macrophages to assess SPARC function.
  • Analysis of SPARC's effect on gene expression, signaling pathways (TLR4, IRF3/7, STAT1), and cellular metabolism.
  • In vivo studies with adipocyte-specific SPARC deletion in aging mice.

Main Results:

  • Sustained CR inhibited SPARC in humans; obesity elevated SPARC.
  • SPARC promoted pro-inflammatory macrophage phenotypes via ISG induction through IRF3/7, TLR4, TBK1, IFN-β, and STAT1 signaling.
  • SPARC impaired mitochondrial respiration and required glycolysis for ISG induction.
  • The N-terminal acidic domain of SPARC was essential for ISG induction.
  • Adipocyte-specific SPARC deletion reduced inflammation and extended health span in aging mice.

Conclusions:

  • SPARC acts as an immunometabolic checkpoint, linking inflammation and interferon responses.
  • SPARC inhibition by CR may contribute to its health benefits.
  • Targeting SPARC presents a potential therapeutic strategy to combat age-related metabolic dysfunction and functional decline.
Keywords:
SPARCTLR4caloric restrictioninflammationinterferon-stimulated genemacrophagematricellular protein

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