title: A unique role for p53 in the regulation of M2 macrophage polarization.
abstract: P53 is critically important in preventing oncogenesis but its role in inflammation in general and in the function of inflammatory macrophages in particular is not clear. Here, we show that bone marrow-derived macrophages exhibit endogenous p53 activity, which is increased when macrophages are polarized to the M2 (alternatively activated macrophage) subtype. This leads to reduced expression of M2 genes. Nutlin-3a, which destabilizes the p53/MDM2 (mouse double minute 2 homolog) complex, promotes p53 activation and further downregulates M2 gene expression. In contrast, increased expression of M2 genes was apparent in M2-polarized macrophages from p53-deficient and p53 mutant mice. Furthermore, we show, in mice, that p53 also regulates M2 polarization in peritoneal macrophages from interleukin-4-challenged animals and that nutlin-3a retards the development of tolerance to Escherichia coli lipopolysaccharide. P53 acts via transcriptional repression of expression of c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) gene by directly associating with its promoter. These data establish a role for the p53/MDM2/c-MYC axis as a physiological 'brake' to the M2 polarization process. This work reveals a hitherto unknown role for p53 in macrophages, provides further insight into the complexities of macrophage plasticity and raises the possibility that p53-activating drugs, many of which are currently being trialled clinically, may have unforeseen effects on macrophage function.
authors.affiliation: p53 Laboratory, A*Star, 8A Biomedical Grove, Immunos, Singapore 138648.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Neurobiology Program, Life Science Institute and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: D S W
authors.initials: DS
authors.lastname: Ng
authors.affiliation: Division of Medical Sciences, National Cancer Centre, Singapore and NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
authors.forename: W-C
authors.initials: WC
authors.lastname: Mah
authors.affiliation: Singapore Immunology Network, A*Star, Singapore.
authors.forename: F F
authors.initials: FF
authors.lastname: Almeida
authors.affiliation: p53 Laboratory, A*Star, 8A Biomedical Grove, Immunos, Singapore 138648.
authors.forename: S A
authors.initials: SA
authors.lastname: Rahmat
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: V K
authors.initials: VK
authors.lastname: Rao
authors.affiliation: Singapore Institute of Clinical Sciences, A*Star, Singapore.
authors.forename: S C
authors.initials: SC
authors.lastname: Leow
authors.affiliation: Singapore Immunology Network, A*Star, Singapore.
authors.forename: F
authors.initials: F
authors.lastname: Laudisi
authors.affiliation: Neurobiology Program, Life Science Institute and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: M T
authors.initials: MT
authors.lastname: Peh
authors.affiliation: p53 Laboratory, A*Star, 8A Biomedical Grove, Immunos, Singapore 138648.
authors.forename: A M
authors.initials: AM
authors.lastname: Goh
authors.affiliation: Microscopy Unit, Institute of Medical Biology, A*Star, Singapore.
authors.forename: J S Y
authors.initials: JS
authors.lastname: Lim
authors.affiliation: Microscopy Unit, Institute of Medical Biology, A*Star, Singapore.
authors.forename: G D
authors.initials: GD
authors.lastname: Wright
authors.affiliation: Singapore Immunology Network, A*Star, Singapore.
authors.forename: A
authors.identifier: 0000000317442430
authors.initials: A
authors.lastname: Mortellaro
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: R
authors.initials: R
authors.lastname: Taneja
authors.affiliation: Singapore Immunology Network, A*Star, Singapore.
authors.forename: F
authors.initials: F
authors.lastname: Ginhoux
authors.affiliation: 1] Division of Medical Sciences, National Cancer Centre, Singapore and NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore [2] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore and Cancer and Stem Cell Biology Program, DUKE-NUS Graduate Medical School, Singapore.
authors.forename: C G
authors.initials: CG
authors.lastname: Lee
authors.affiliation: Neurobiology Program, Life Science Institute and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: P K
authors.initials: PK
authors.lastname: Moore
authors.affiliation: p53 Laboratory, A*Star, 8A Biomedical Grove, Immunos, Singapore 138648.
authors.forename: D P
authors.initials: DP
authors.lastname: Lane
mesh_terms: D000818:Animals; D016764:Cell Polarity; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism; D008070:Lipopolysaccharides; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000276:immunology / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology
chemical_list: D007093:Imidazoles; D008070:Lipopolysaccharides; C489428:Myc protein, mouse; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D015847:Interleukin-4; C482205:nutlin 3; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2