RationnelRecently, it has been shown that the genomic locus CDKN2A, which partially codes for p16^ink4a, is associated with the development of type 2 diabetes (T2D) in several populations. P16^ink4ais a tumour suppressor that controls the cell cycle and cellular senescence. Macrophages are known to play an instrumental role during the development of T2D. They can present different polarization states : classical (M1 : pro-inflammatory) or alternative (M2 : anti-inflammatory). We therefore aim to investigate the role of p16^ink4aduring differentiation and polarization of human monocyte-derived macrophages.Matériels et Méthodesp16^ink4amRNA and protein levels were measured in classically differentiated and in alternatively differentiated (by IL4) human monocyte-derived macrophages. To explore the role of p16^ink4a, its levels were lowered by RNA interference, after which macrophage phenotype was analyzed. In addition, p16^ink4aexpression levels were compared between ATMs and monocyte-derived macrophages isolated from obese patients.Résultatsp16^ink4awas induced during classical macrophage differentiation. Interestingly, alternative differentiation inhibited p16^ink4aexpression. Silencing p16^ink4aresulted in an increase of a number of M2 marker genes (MR, AMAC1, TGFbeta, IL1Ra, IL10, MMP2, ItgB). Surprisingly, despite this M2 phenotype, these cells had increased responses to LPS, shown by amplified expression of pro-inflammatory markers as Cox2, Mcp1, and TNF, possibly as the result from an increase in Tlr4 expression. Additionally, these cells secreted higher levels of TNF protein.DiscussionThis phenotype closely resembles the one of adipose tissue macrophages (ATMs). Confirming the inverse correlation of p16^ink4aexpression levels with an ATM phenotype, we found that in ATMs from obese patients, p16^ink4alevels were lower than in monocyte-derived macrophages of the same subjects.ConclusionSuppression of p16^ink4ain human macrophages leads to a phenotype resembling that of ATMs. P16^ink4amay thus play a role in ATM development and function.