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

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, p16INK4A 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, p16INK4A levels were studied during macrophage differentiation and polarisation of monocytes isolated from healthy donors.

Cellular senescence impact on immune cell fate and function

“…Interestingly, the expression and role of senescence markers, such as p16 INK4a and p14/p19 ARF , in murine bone marrow‐derived macrophages (BMDM), as well as in human adipose tissue macrophages, have been recently described (Cudejko et al ., 2011; Fuentes et al ., 2011). Cudejko et al .…”

“…Interestingly, incubation with IL‐4, the M2 polarization factor, further increased the expression of M2‐associated genes in p16 INK4a ‐deficient BMDM. Conversely, incubation with the classical M1 polarization factors, IFN‐γ and LPS, led to a decrease in IL‐6, TNF‐α, and MCP‐1 expression in p16 INK4a ‐deficient BMDM (Cudejko et al ., 2011; Fuentes et al ., 2011). Similarly, p16 INK4a expression was low in human adipose tissue macrophages and silencing p16 INK4a expression in monocyte‐derived macrophages increased mRNA expression of M2 markers such as MRC1 and AMAC1 (Fuentes et al ., 2011).…”

“…Conversely, incubation with the classical M1 polarization factors, IFN‐γ and LPS, led to a decrease in IL‐6, TNF‐α, and MCP‐1 expression in p16 INK4a ‐deficient BMDM (Cudejko et al ., 2011; Fuentes et al ., 2011). Similarly, p16 INK4a expression was low in human adipose tissue macrophages and silencing p16 INK4a expression in monocyte‐derived macrophages increased mRNA expression of M2 markers such as MRC1 and AMAC1 (Fuentes et al ., 2011). Moreover, in agreement with the murine studies, in vitro IL‐4‐polarized human M2 macrophages expressed lower levels of p16 INK4a than in vitro IFN‐γ‐polarized M1 (Cudejko et al ., 2011; Fuentes et al ., 2011).…”

“…Similarly, p16 INK4a expression was low in human adipose tissue macrophages and silencing p16 INK4a expression in monocyte‐derived macrophages increased mRNA expression of M2 markers such as MRC1 and AMAC1 (Fuentes et al ., 2011). Moreover, in agreement with the murine studies, in vitro IL‐4‐polarized human M2 macrophages expressed lower levels of p16 INK4a than in vitro IFN‐γ‐polarized M1 (Cudejko et al ., 2011; Fuentes et al ., 2011). Similar polarizing properties were obtained with primary macrophages that can become senescent after 2 weeks of in vitro expansion, or upon ectopic p16 INK4a expression.…”

Protective Effect of 2-Dodecyl-6-Methoxycyclohexa-2, 5-Diene-1, 4-Dione, Isolated from Averrhoa Carambola L., Against Palmitic Acid-Induced Inflammation and Apoptosis in Min6 Cells by Inhibiting the TLR4-MyD88-NF-κB Signaling Pathway

“…The extrinsic pathway, also known as the death receptor pathway, initiates the Cleaved-Caspase-8 dependent signal cascade [6]. The intrinsic pathway, also known as the mitochondrial pathway, involves the release of apoptotic proteins, such as cytochrome c, Cleaved-Caspase-3, and Cleaved-Caspase-9 [7]. Bcl-2 family proteins play an important role in intrinsic apoptosis pathway [8].…”