Li L, Ng D S W, Mah W-C, Almeida F F, Rahmat S A, Rao V K, Leow S C, Laudisi F, Peh M T, Goh A M, Lim J S Y, Wright G D, Mortellaro A, Taneja R, Ginhoux F, Lee C G, Moore P K, Lane D P
p53 Laboratory, A*Star, 8A Biomedical Grove, Immunos, Singapore 138648.
Neurobiology Program, Life Science Institute and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Cell Death Differ. 2015 Jul;22(7):1081-93. doi: 10.1038/cdd.2014.212. Epub 2014 Dec 19.
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.
P53在预防肿瘤发生中至关重要，但其在一般炎症尤其是炎症性巨噬细胞功能中的作用尚不清楚。在此，我们表明骨髓来源的巨噬细胞具有内源性p53活性，当巨噬细胞极化为M2（替代性激活巨噬细胞）亚型时，该活性会增加。这导致M2基因表达降低。Nutlin-3a可使p53/MDM2（小鼠双微体2同源物）复合物不稳定，促进p53激活并进一步下调M2基因表达。相反，在p53缺陷和p53突变小鼠的M2极化巨噬细胞中，M2基因表达明显增加。此外，我们在小鼠中发现，p53还调节来自白细胞介素-4刺激动物的腹膜巨噬细胞中的M2极化，并且Nutlin-3a会延缓对大肠杆菌脂多糖耐受性的发展。P53通过直接与其启动子结合，对c-Myc（v-myc禽骨髓细胞瘤病毒癌基因同源物）基因的表达进行转录抑制来发挥作用。这些数据确立了p53/MDM2/c-MYC轴作为M2极化过程的生理“刹车”的作用。这项工作揭示了p53在巨噬细胞中迄今未知的作用，进一步深入了解了巨噬细胞可塑性的复杂性，并提出了目前正在临床试用的许多p53激活药物可能对巨噬细胞功能产生不可预见影响的可能性。
