☆ 4.7 Article

Downregulation of the tumour suppressor p16INK4A contributes to the polarisation of human macrophages toward an adipose tissue macrophage (ATM)-like phenotype

DIABETOLOGIA (2011)

期刊

DIABETOLOGIA

卷 54, 期 12, 页码 3150-3156

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SPRINGER

DOI: 10.1007/s00125-011-2324-0

关键词

Adipose tissue macrophage; CDKN2A; Inflammation; Macrophage polarisation; Senescence; Type 2 diabetes

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Endocrinology & Metabolism

资金

EU [EIF 040851, PIEF-GA-2009-23522, 201608]
EFSD/GlaxoSmithKline
Spanish Government MEC (Ministerio de Educacion y Ciencia)
Fondation pour la Recherche Medicale [DCV20070409276]

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Aims/hypothesis Human adipose tissue macrophages (ATMs) display an alternatively activated (M2) phenotype, but are still able to produce excessive inflammatory mediators. However, the processes driving this particular ATM phenotype are not understood. Genome-wide association studies associated the CDKN2A locus, encoding the tumour suppressor p16(INK4A), with the development of type 2 diabetes. In the present study, p16(INK4A) levels in human ATMs and the role of p16(INK4A) in acquiring the ATM phenotype were assessed. Methods Gene expression of p16(INK4A) in ATMs was analysed and compared with that in monocyte-derived macrophages (MDMs) from obese patients or with macrophages from human atherosclerotic plaques (AMs). Additionally, p16(INK4A) levels were studied during macrophage differentiation and polarisation of monocytes isolated from healthy donors. The role of p16(INK4A) in MDMs from healthy donors was investigated by small interfering (si) RNA-mediated silencing or adenovirus-mediated overproduction of p16(INK4A). Results Compared with MDMs and AMs, ATMs from obese patients expressed lower levels of p16(INK4A). In vitro, IL-4-induced M2 polarisation resulted in lower p16(INK4A) protein levels after differentiation of monocytes from healthy donors in macrophages. Silencing of p16(INK4A) in MDMs mediated by siRNA increased the expression of M2 marker genes and enhanced the response to lipopolysaccharide (LPS), to give a phenotype resembling that of ATM. By contrast, adenovirus-mediated overproduction of p16(INK4A) in MDMs diminished M2 marker gene expression and the response to LPS. Western blot analysis revealed that p16(INK4A) overproduction inhibits LPS- and palmitate-induced Toll-like receptor 4 (TLR4)-nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-kappa B) signalling. Conclusions/interpretation These results show that p16(INK4A) inhibits the acquisition of the ATM phenotype. The age-related increase in p16(INK4A) level may thus influence normal ATM function and contribute to type 2 diabetes risk.

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Mitochondrially targeted tamoxifen alleviates markers of obesity and type 2 diabetes mellitus in mice

Eliska Vacurova, Jaroslava Trnovska, Petr Svoboda, Vojtech Skop, Vendula Novosadova, David Pajuelo Reguera, Silvia Petrezselyova, Benoit Piavaux, Berwini Endaya, Frantisek Spoutil, Dagmar Zudova, Jan Stursa, Magdalena Melcova, Zuzana Bielcikova, Lukas Werner, Jan Prochazka, Radislav Sedlacek, Martina Huttl, Sona Stemberkova Hubackova, Martin Haluzik, Jiri Neuzil

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