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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

Authors: 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

Published in: Diabetologia | Issue 12/2011

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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Fuentes L, Roszer T, Ricote M (2010) Inflammatory mediators and insulin resistance in obesity: role of nuclear receptor signaling in macrophages. Mediators Inflamm 2010:219583PubMedCrossRef

Cinti S, Mitchell G, Barbatelli G et al (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46:2347–2355PubMedCrossRef

Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461PubMedCrossRef

Porcheray F, Viaud S, Rimaniol AC et al (2005) Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 142:481–489PubMed

Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175–184PubMedCrossRef

Prieur X, Mok CY, Velagapudi VR et al (2011) Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes 60:797–809PubMedCrossRef

Dalmas E, Clement K, Guerre-Millo M (2011) Defining macrophage phenotype and function in adipose tissue. Trends Immunol 32:307–314PubMedCrossRef

Zeyda M, Farmer D, Todoric J et al (2007) Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. Int J Obes (Lond) 31:1420–1428CrossRef

Sharpless NE (2005) INK4a/ARF: a multifunctional tumor suppressor locus. Mutat Res 576:22–38PubMedCrossRef

10.

Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA (1994) Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368:753–756PubMedCrossRef

11.

Huschtscha LI, Reddel RR (1999) p16(INK4a) and the control of cellular proliferative life span. Carcinogenesis 20:921–926PubMedCrossRef

12.

Li H, Collado M, Villasante A et al (2009) The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460:1136–1139PubMedCrossRef

13.

Saxena R, Voight BF, Lyssenko V et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336PubMedCrossRef

14.

Mayi TH, Duhem C, Copin C et al (2010) Visfatin is induced by peroxisome proliferator-activated receptor gamma in human macrophages. FEBS J 277:3308–3320PubMed

15.

Gizard F, Amant C, Barbier O et al (2005) PPAR alpha inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a. J Clin Invest 115:3228–3238PubMedCrossRef

16.

Bouhlel MA, Derudas B, Rigamonti E et al (2007) PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6:137–143PubMedCrossRef

17.

Carpenter S, O'Neill LA (2009) Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins. Biochem J 422:1–10PubMedCrossRef

18.

Liew FY, Xu D, Brint EK, O'Neill LA (2005) Negative regulation of Toll-like receptor-mediated immune responses. Nat Rev Immunol 5:446–458PubMedCrossRef

19.

Garaulet M, Perez-Llamas F, Perez-Ayala M et al (2001) Site-specific differences in the fatty acid composition of abdominal adipose tissue in an obese population from a Mediterranean area: relation with dietary fatty acids, plasma lipid profile, serum insulin, and central obesity. Am J Clin Nutr 74:585–591PubMed

20.

Nguyen MT, Favelyukis S, Nguyen AK et al (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282:35279–35292PubMedCrossRef

21.

Bourlier V, Zakaroff-Girard A, Miranville A et al (2008) Remodeling phenotype of human subcutaneous adipose tissue macrophages. Circulation 117:806–815PubMedCrossRef

22.

Wentworth JM, Naselli G, Brown WA et al (2010) Pro-inflammatory CD11c⁺CD206⁺ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes 59:1648–1656PubMedCrossRef

23.

Nasu K, Kohsaka H, Nonomura Y et al (2000) Adenoviral transfer of cyclin-dependent kinase inhibitor genes suppresses collagen-induced arthritis in mice. J Immunol 165:7246–7252PubMed

24.

Chen M, Capps C, Willerson JT, Zoldhelyi P (2002) E2F-1 regulates nuclear factor-kappaB activity and cell adhesion: potential antiinflammatory activity of the transcription factor E2F-1. Circulation 106:2707–2713PubMedCrossRef

25.

Chiang SH, Bazuine M, Lumeng CN et al (2009) The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 138:961–975PubMedCrossRef

26.

Arkan MC, Hevener AL, Greten FR et al (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198PubMedCrossRef

27.

Saberi M, Woods NB, de Luca C et al (2009) Hematopoietic cell-specific deletion of Toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab 10:419–429PubMedCrossRef

28.

Wolff B, Naumann M (1999) INK4 cell cycle inhibitors direct transcriptional inactivation of NF-kappaB. Oncogene 18:2663–2666PubMedCrossRef

29.

Lovren F, Pan Y, Quan A et al (2010) Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages. Am J Physiol Heart Circ Physiol 299:H656–H663PubMedCrossRef

30.

Hagemann T, Lawrence T, McNeish I et al (2008) “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205:1261–1268PubMedCrossRef

31.

Hackanson B, Guo Y, Lubbert M (2005) The silence of the genes: epigenetic disturbances in haematopoietic malignancies. Expert Opin Ther Targets 9:45–61PubMedCrossRef

32.

Krishnamurthy J, Ramsey MR, Ligon KL et al (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453–457PubMedCrossRef

33.

Janzen V, Forkert R, Fleming HE et al (2006) Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443:421–426PubMed

Title: Downregulation of the tumour suppressor p16INK4A contributes to the polarisation of human macrophages toward an adipose tissue macrophage (ATM)-like phenotype
Authors: 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
Publication date: 01-12-2011
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 12/2011
Print ISSN: 0012-186X
Electronic 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

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

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Abstract

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