Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction
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
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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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 2

Osteopontin is a critical regulator of adipose tissue and macrophage senescence.

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Osteopontin is a critical regulator of adipose tissue and macrophage sen...
(A) Representative SA-β-Gal staining of VAT from 12-month-old WT and OPN–/– mice (selected from n = 5/group). (B) Immunoblot of VAT from 12-month-old WT and OPN–/– mice. Separate loading controls (β-actin) are presented due to the noncontemporaneous run of the same lysates. (C) Representative immunofluorescence of VAT (arrowheads: p16, p53, and p21). (D) Percentage of p16+ cells (n = 5/group, same data from the aged WT as in Figure 1). Representative immunofluorescence (E) and quantification (F) of p16+ in the percentage of CD68+ cells in VAT (n = 4/group). FACS gating strategy (G) and quantification (H) of p16+ in CD11b+ F4/80+ ATMs from VAT in indicated groups (n = 4/group). (I) Representative images and quantification (n = 5 mice/group) of p16 in VAT of 12-month-old WT treated with AA vs. vehicle (VEH); arrowheads: p16+ cells. (J) Representative images and quantification of p16+ in the percentage of CD68+ in VAT (n = 7–10 mice/group). Arrowheads: double-positive ATMs. (K) Mean fluorescent intensity ratio (MFIR) of OPN receptor expression in CD11b+ F4/80+ ATMs from VAT of 3- and 12-month-old WT mice (n = 3–7 mice/group). (L) OPN receptor expression in CD11b+ F4/80+ ATMs from BMDMs of 3- and 12-month-old WT mice (n = 6–7 mice/group). SA-β-Gal (M) and p16 (N) staining in BMDMs (from 3-month-old WT mice) treated with recombined OPN protein or VEH ± CD44 blocking antibody (n = 8–9/condition). (O) Protocol of in vivo implantation of Matrigel enriched with OPN protein or VEH. (P) Representative immunofluorescence of excised Matrigel after 14 days of implantation (selected from n = 3 mice/group). Quantification of relative CD68+ area (Q) and percentage of p16+ cells (R) (n = 3 mice/group). All scale bars: 50 μm. Data are presented as original images (A–C, E, G, I, J, M, N, and P) or individual values with mean ± SEM and analyzed with 2-tailed, unpaired Student’s t test (D, F, I–L, Q, and R) or 1-way ANOVA with Tukey’s post hoc test (F, H, M, and N); ns, nonsignificant; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.