TY - JOUR
T1 - The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging
AU - Ryu, Seungjin
AU - Sidorov, Sviatoslav
AU - Ravussin, Eric
AU - Artyomov, Maxim
AU - Iwasaki, Akiko
AU - Wang, Andrew
AU - Dixit, Vishwa Deep
N1 - Funding Information:
We thank all investigators and staff involved in coordinating and executing the CALERIE-II clinical trial. We thank Dr. Gerald Shadel for helpful discussion and protocols to quantify mtDNA. S.R. is a recipient of AFAR postdoctoral fellowship. This research was supported in part by NIH grants AG031797 , AG045712 , P01AG051459 , AR070811 , the Glenn Foundation for Medical Research , and Cure Alzheimer’s Fund ( CAF ) to V.D.D. and an Aging Biology Foundation grant to M.A.; CALERIE study was funded by the National Institute on Aging grants U01AG022132 , U01AG020478 , U01AG020487 , and U01AG020480 .
Funding Information:
We thank all investigators and staff involved in coordinating and executing the CALERIE-II clinical trial. We thank Dr. Gerald Shadel for helpful discussion and protocols to quantify mtDNA. S.R. is a recipient of AFAR postdoctoral fellowship. This research was supported in part by NIH grants AG031797, AG045712, P01AG051459, AR070811, the Glenn Foundation for Medical Research, and Cure Alzheimer's Fund (CAF) to V.D.D. and an Aging Biology Foundation grant to M.A.; CALERIE study was funded by the National Institute on Aging grants U01AG022132, U01AG020478, U01AG020487, and U01AG020480. S.R. performed experiments, data analysis, and prepared manuscript. S.S. performed RNA sequencing analysis. M.A. supervised the RNA sequencing analysis. E.R. was involved in the design of CALERIE study and BARIA studies and supervised the clinical and energy expenditure analyses. A.I. and A.W. generated the IR3-, IRF7-, cGAS-, TLR4-, Myd88-, IFNAR-deficient mouse models, participated in experimental design, and helped with data interpretation. V.D.D. conceived the project and helped with data analysis, interpretation, and wrote the manuscript. All authors participated in manuscript preparation. The authors declare no competing interests.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/9/13
Y1 - 2022/9/13
N2 - 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.
AB - 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.
KW - SPARC
KW - TLR4
KW - caloric restriction
KW - inflammation
KW - interferon-stimulated gene
KW - macrophage
KW - matricellular protein
UR - http://www.scopus.com/inward/record.url?scp=85136657701&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2022.07.007
DO - 10.1016/j.immuni.2022.07.007
M3 - Article
C2 - 35963236
AN - SCOPUS:85136657701
SN - 1074-7613
VL - 55
SP - 1609-1626.e7
JO - Immunity
JF - Immunity
IS - 9
ER -