title: p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages.
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.
authors.affiliation: Université Lille Nord de France, Lille, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Cudejko
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Wouters
authors.forename: Lucía
authors.initials: L
authors.lastname: Fuentes
authors.forename: Sarah Anissa
authors.initials: SA
authors.lastname: Hannou
authors.forename: Charlotte
authors.initials: C
authors.lastname: Paquet
authors.forename: Kadiombo
authors.initials: K
authors.lastname: Bantubungi
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bouchaert
authors.forename: Jonathan
authors.initials: J
authors.lastname: Vanhoutte
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fleury
authors.forename: Patrick
authors.initials: P
authors.lastname: Remy
authors.forename: Anne
authors.initials: A
authors.lastname: Tailleux
authors.forename: Giulia
authors.initials: G
authors.lastname: Chinetti-Gbaguidi
authors.forename: David
authors.initials: D
authors.lastname: Dombrowicz
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Réjane
authors.initials: R
authors.lastname: Paumelle
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D019942:Genes, p16; D051550:I-kappa B Kinase / Q000502:physiology; D007249:Inflammation / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011828:Radiation Chimera; D050794:STAT1 Transcription Factor / Q000502:physiology*; D050800:STAT6 Transcription Factor / Q000502:physiology; D012552:Schistosomiasis / Q000276:immunology; D015398:Signal Transduction
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016207:Cytokines; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D007371:Interferon-gamma; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse