Downregulation of the tumour suppressor p16^sup INK4A^ contributes to the polarisation of human macrophages toward an adipose tissue macrophage (ATM)-like phenotype

• Published in: Diabetologia 2011-12, Vol.54 (12), p.3150
• Main Authors: Fuentes, L, Wouters, K, Hannou, S A, Cudejko, C, Rigamonti, E, Mayi, T H, Derudas, B, Pattou, F, Chinetti-gbaguidi, G, Staels, B, Paumelle, R
• Format: Article
• Language: English
• Subjects: Adenoviruses; Adipocytes; Atherosclerosis; Body fat; Cell cycle; Chemokines; Cyclin-dependent kinases; Cytokines; Diabetes; Gene expression; Genotype & phenotype; Inflammation; Kinases; Obesity; Polypeptides; Senescence
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-011-2324-0

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^sup INK4A^, with the development of type 2 diabetes. In the present study, p16^sup INK4A^ levels in human ATMs and the role of p16^sup INK4A^ in acquiring the ATM phenotype were assessed. Gene expression of p16 ^sup 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^sup INK4A^ levels were studied during macrophage differentiation and polarisation of monocytes isolated from healthy donors. The role of p16^sup INK4A^ in MDMs from healthy donors was investigated by small interfering (si)RNA-mediated silencing or adenovirus-mediated overproduction of p16^sup INK4A^. Compared with MDMs and AMs, ATMs from obese patients expressed lower levels of p16 ^sup INK4A^. In vitro, IL-4-induced M2 polarisation resulted in lower p16^sup INK4A^ protein levels after differentiation of monocytes from healthy donors in macrophages. Silencing of p16^sup 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^sup INK4A^ in MDMs diminished M2 marker gene expression and the response to LPS. Western blot analysis revealed that p16^sup INK4A^ overproduction inhibits LPS- and palmitate-induced Toll-like receptor 4 (TLR4)-nuclear factor of κ light polypeptide gene enhancer in B cells (NF-κB) signalling. These results show that p16^sup INK4A^ inhibits the acquisition of the ATM phenotype. The age-related increase in p16^sup INK4A^ level may thus influence normal ATM function and contribute to type 2 diabetes risk.[PUBLICATION ABSTRACT]