p 16 deficiency promotes IL - 4 - induced polarization and inhibits INK 4 a proinflammatory signaling in macrophages

The locus, which contains the tumor suppressor gene p16 , is associated with an increased risk of age-related CDKN2A INK4a inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize towards classically (CAM ) or alternatively (AAM ) activated macrophages. However, the molecular mechanisms φ φ underlying the acquisition of these phenotypes are not well defined. Here, we show that p16 -deficiency (p16 ) modulates the macrophage phenotype. Transcriptome analysis revealed that p16 INK4a / − − / − − bone marrow-derived macrophages (BMDM) exhibit a phenotype resembling interleukin (IL)-4-induced macrophage polarization. In line with this observation, p16 BMDM displayed a decreased response to classically polarizing IFN and LPS and an increased / − − γ sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16 bone marrow displayed higher hepatic / − − AAM marker expression levels upon infection, an model of AAM phenotype-skewing. Surprisingly, φ Schistosoma mansoni in vivo φ p16 BMDM did not display increased IL-4-induced STAT6 signaling, but decreased IFN -induced STAT1 and LPS-induced IKK , / − − γ α phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of β STAT1 and IKK , . These findings identify p16 as a modulator of macrophage activation and polarization via the JAK2-STAT1 α β INK4a pathway with possible roles in inflammatory diseases. MESH