p16INK4a deficiency promotes IL-4–induced polarization and inhibits proinflammatory signaling in macrophages
- 1 September 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 118 (9), 2556-2566
- https://doi.org/10.1182/blood-2010-10-313106
Abstract
The CDKN2A locus, which contains the tumor suppressor gene p16INK4a, is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMφ) or alternatively (AAMφ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16INK4a deficiency (p16−/−) modulates the macrophage phenotype. Transcriptome analysis revealed that p16−/− BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4–induced macrophage polarization. In line with this observation, p16−/− BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16−/− BM displayed higher hepatic AAMφ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMφ phenotype skewing. Surprisingly, p16−/− BMDMs did not display increased IL-4–induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)–induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16INK4a as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.Keywords
This publication has 51 references indexed in Scilit:
- Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappa BProceedings of the National Academy of Sciences of the United States of America, 2009
- Kupffer cells in non-alcoholic fatty liver disease: The emerging viewJournal of Hepatology, 2009
- The CDK domain of p21 is a suppressor of IL‐1β‐mediated inflammation in activated macrophagesEuropean Journal of Immunology, 2009
- A common variant of the p16INK4a genetic region is associated with physical function in older peopleMechanisms of Ageing and Development, 2007
- A Common Allele on Chromosome 9 Associated with Coronary Heart DiseaseScience, 2007
- Macrophage-specific PPARγ controls alternative activation and improves insulin resistanceNature, 2007
- Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signalingProceedings of the National Academy of Sciences of the United States of America, 2006
- Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammationCell Metabolism, 2006
- Alternative activation of macrophagesNature Reviews Immunology, 2003
- A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4Nature, 1993