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01.12.2011 | Article

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

verfasst von: L. Fuentes, K. Wouters, S. A. Hannou, C. Cudejko, E. Rigamonti, T. H. Mayi, B. Derudas, F. Pattou, G. Chinetti-Gbaguidi, B. Staels, R. Paumelle

Erschienen in: Diabetologia | Ausgabe 12/2011

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Abstract

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 κ light polypeptide gene enhancer in B cells (NF-κB) 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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Titel: Downregulation of the tumour suppressor p16INK4A contributes to the polarisation of human macrophages toward an adipose tissue macrophage (ATM)-like phenotype
verfasst von: L. Fuentes
K. Wouters
S. A. Hannou
C. Cudejko
E. Rigamonti
T. H. Mayi
B. Derudas
F. Pattou
G. Chinetti-Gbaguidi
B. Staels
R. Paumelle
Publikationsdatum: 01.12.2011
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 12/2011
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2324-0

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

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Aims/hypothesis

Methods

Results

Conclusions/interpretation

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