Immune checkpoint protein VSIG4 as a biomarker of aging in murine adipose tissue

• Published in: Aging cell Vol. 19; no. 10; pp. e13219 - n/a
• Main Authors: Hall, Brandon M., Gleiberman, Anatoli S., Strom, Evguenia, Krasnov, Peter A., Frescas, David, Vujcic, Slavoljub, Leontieva, Olga V., Antoch, Marina P., Kogan, Valeria, Koman, Igor E., Zhu, Yi, Tchkonia, Tamara, Kirkland, James L., Chernova, Olga B., Gudkov, Andrei V.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2020; John Wiley and Sons Inc
• Subjects: Adaptive immunity; Adipose tissue; Adipose Tissue, White - metabolism; Adipose tissues; Age; Aging; Aging - metabolism; Analysis; Animals; B7 antigen; Biomarkers; Biomarkers - metabolism; Body fat; Chemokines; Cytokines; Female; Frailty; frailty index; Gene expression; Homeostasis; Immune checkpoint; Immunosenescence; Inbreeding; Inflammation; Inflammatory diseases; Lung cancer; macrophage; Macrophages; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; mouse; Original; Proteins; Receptors, Complement - metabolism; Ribonucleic acid; RNA; Stroma; VSIG4; Xenografts; mouse; inflammation; immune checkpoint; adipose tissue; frailty index; macrophage; VSIG4; aging
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.13219

Adipose tissue is recognized as a major source of systemic inflammation with age, driving age‐related tissue dysfunction and pathogenesis. Macrophages (Mφ) are central to these changes yet adipose tissue Mφ (ATMs) from aged mice remain poorly characterized. To identify biomarkers underlying changes in aged adipose tissue, we performed an unbiased RNA‐seq analysis of ATMs from young (8‐week‐old) and healthy aged (80‐week‐old) mice. One of the genes identified, V‐set immunoglobulin‐domain‐containing 4 (VSIG4/CRIg), encodes a Mφ‐associated complement receptor and B7 family‐related immune checkpoint protein. Here, we demonstrate that Vsig4 expression is highly upregulated with age in perigonadal white adipose tissue (gWAT) in two mouse strains (inbred C57BL/6J and outbred NIH Swiss) independent of gender. The accumulation of VSIG4 was mainly attributed to a fourfold increase in the proportion of VSIG4+ ATMs (13%–52%). In a longitudinal study, VSIG4 expression in gWAT showed a strong correlation with age within a cohort of male and female mice and correlated strongly with physiological frailty index (PFI, a multi‐parameter assessment of health) in male mice. Our results indicate that VSIG4 is a novel biomarker of aged murine ATMs. VSIG4 expression was also found to be elevated in other aging tissues (e.g., thymus) and was strongly induced in tumor‐adjacent stroma in cases of spontaneous and xenograft lung cancer models. VSIG4 expression was recently associated with cancer and several inflammatory diseases with diagnostic and prognostic potential in both mice and humans. Further investigation is required to determine whether VSIG4‐positive Mφ contribute to immunosenescence and/or systemic age‐related deficits. Adipocytes were removed from gonadal fat (gWAT) of old and young mice, and remaining cells were fractionated into cells capable (e.g., Mφ) and incapable of phagocyting magnetic iron particles. RNA was sequenced and analyzed to identify aging‐associated macrophage‐specific transcripts. Identified candidates were validated, and VSIG4 was confirmed a macrophageal biomarker correlating with chronological and biological age.