Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction
Daigo Sawaki, … , Gabor Czibik, Geneviève Derumeaux
Daigo Sawaki, … , Gabor Czibik, Geneviève Derumeaux
Published April 24, 2023
Citation Information: JCI Insight. 2023;8(8):e145811. https://doi.org/10.1172/jci.insight.145811.
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Research Article Aging Immunology

Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction

Abstract

Adipose tissue macrophages (ATMs) play an important role in obesity and inflammation, and they accumulate in adipose tissue (AT) with aging. Furthermore, increased ATM senescence has been shown in obesity-related AT remodeling and dysfunction. However, ATM senescence and its role are unclear in age-related AT dysfunction. Here, we show that ATMs (a) acquire a senescence-like phenotype during chronological aging; (b) display a global decline of basic macrophage functions such as efferocytosis, an essential process to preserve AT homeostasis by clearing dysfunctional or apoptotic cells; and (c) promote AT remodeling and dysfunction. Importantly, we uncover a major role for the age-associated accumulation of osteopontin (OPN) in these processes in visceral AT. Consistently, loss or pharmacologic inhibition of OPN and bone marrow transplantation of OPN–/– mice attenuate the ATM senescence-like phenotype, preserve efferocytosis, and finally restore healthy AT homeostasis in the context of aging. Collectively, our findings implicate pharmacologic OPN inhibition as a viable treatment modality to counter ATM senescence-mediated AT remodeling and dysfunction during aging.

Authors

Daigo Sawaki, Yanyan Zhang, Amel Mohamadi, Maria Pini, Zaineb Mezdari, Larissa Lipskaia, Suzain Naushad, Lucille Lamendour, Dogus Murat Altintas, Marielle Breau, Hao Liang, Maissa Halfaoui, Thaïs Delmont, Mathieu Surenaud, Déborah Rousseau, Takehiko Yoshimitsu, Fawzia Louache, Serge Adnot, Corneliu Henegar, Philippe Gual, Gabor Czibik, Geneviève Derumeaux

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Figure 4

Role of OPN in age-related ATM dysfunction.

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Role of OPN in age-related ATM dysfunction. (A) Representative TUNEL/CD4...
(A) Representative TUNEL/CD45 immunofluorescence of VAT from 3- and 12-month WT and OPN–/– mice. Green arrowheads, single TUNEL+ cells; white arrowheads, TUNEL/CD45 double-positive cells. (B) Quantification of colocalization of TUNEL+ and CD45+ cells in percentage of total cell number (n = 6 mice/group). (C) Quantification of the distance between TUNEL+ and CD45+ cells (arbitrary units [AU]). (D) Representative confocal images of TUNEL/CD68 labeling in fresh VAT of 12-month-old WT and OPN–/– mice (selected from n = 3 mice/group). (E) Representative cleaved caspase-3/CD45 immunofluorescence of VAT from 12-month WT and OPN–/– mice. Arrowheads, double-positive cells. (F) Quantification of colocalization of cleaved caspase-3 and CD45 in percentage of total CD45+ cell number (n = 3 mice/group). (G) Representative γH2AX/CD45 immunofluorescence of VAT from 12-month-old WT and OPN–/– mice. Green arrowheads, single γH2AX+ cells; white arrowheads, double-positive cells. (H) Quantification of colocalized γH2AX/CD45 double-positive cells in percentage of total CD45+ cell number (n = 3 mice/group). (I) FACS-based quantification of phagocytosis of pHrodo-labeled human leukemia cells as a function of time in BMDMs derived from 12-month-old WT and OPN–/– mice. Line plots denote chronological quantification of MFI of pHrodo green. (J) qRT-PCR analysis of senescence and efferocytosis-related gene expression in VAT of 3- and 12-month-old WT and OPN–/– mice (n = 4–7 mice/group). (K) FACS-based quantification of phagocytosis as a function of time in WT BMDMs treated with OPN protein vs. vehicle. (L) qRT-PCR analysis of efferocytosis-related gene expression in WT BMDMs treated with 2 doses of OPN protein (n = 4/condition). All scale bars: 50 μm. Data are presented as original images (A, D, E, and G) or individual values with mean ± SEM analyzed with 2-tailed, unpaired Student’s t test (F and H) or 1-way ANOVA with Bonferroni post hoc test (B, C, J, and L) or 2-way ANOVA (I and K); ns, nonsignificant; *P < 0.05, **P < 0.01, ***P < 0.001.