Decreased SPARC in Fat Tissue Reduces Chronic Inflammation

SPARC is one of a number of proteins that mediate interactions between cells and the extracellular matrix. Researchers here note that SPARC is connected to the chronic inflammation of aging, and the relationship between visceral fat tissue and inflammatory signaling, perhaps largely via its influence on whether macrophages adopt inflammatory behaviors in response to their environment. Reducing the amount of SPARC in fat tissue reduces chronic inflammation and thereby improves health, and this may be a meaningful mechanism in the way in which calorie restriction produces lowered inflammation and improved health. Therapies that target SPARC might prove to be useful; any approach that lowers inappropriate inflammatory signaling in later life without impacting necessary inflammatory signaling may be promising.

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.


Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.