p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages. - Archive ouverte HAL Access content directly
Journal Articles Blood Year : 2011

p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages.

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Abstract

The CDKN2A locus, which contains the tumor suppressor gene p16(INK4a), 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 p16(INK4a) 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 p16(INK4a) as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.
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Dates and versions

inserm-00605106 , version 1 (30-06-2011)

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Céline Cudejko, Kristiaan Wouters, Lucía Fuentes, Sarah Anissa Hannou, Charlotte Paquet, et al.. p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages.: p16INK4a function in macrophages. Blood, 2011, 118 (9), pp.2556-66. ⟨10.1182/blood-2010-10-313106⟩. ⟨inserm-00605106⟩
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