A unique role for p53 in the regulation of M2 macrophage polarization.

Macrophages have key roles in the response to stress, injury, infection and inflammation. The M1 (classically activated macrophages) are induced by lipopolysaccharide (LPS) and cytokines such as interferon-γ (IFNγ) and characterized by the expression of a wide range of proinflammatory genes. M2 (alternatively activated macrophages) are induced by T helper type 2 (Th2) cytokines such as interleukin-4 (IL4) and IL13 and express high levels of anti-inflammatory and tissue repair marker genes. M2 macrophages perform immunoregulatory functions including defense against infection, promotion of angiogenesis and wound healing.1 Macrophages exist on a continuum between M1 and M2 subtypes undergoing dynamic changes between these different functional states depending on changes in their microenvironment. This ‘plasticity' involves extensive changes in macrophage gene sets and provides the potential to develop drugs to manipulate the macrophage subtype.2 As such, macrophage polarization, and its molecular basis, has been vigorously researched in recent years. P53 has a crucial role in cancer by controlling the expression of genes involved in apoptosis, cell cycle arrest, metabolism and DNA repair.3 While inflammation is increasingly recognized as a factor in determining the predisposition to cancer,4 the role of p53 in inflammation is not clear. Macrophages from p53−/− mice produce increased quantities of proinflammatory cytokines in response to LPS,5 while peritoneal macrophage count and susceptibility to lethal septic shock are increased in p53−/− mice administered LPS.6 Although a role for p53 in M1 macrophage function has been suggested, there is little information relating to its effect in M2 macrophages. We show here that p53 is important for IL4/IL13-activated M2 macrophage polarization and that this is largely due to repression of transcription of c-MYC (v-myc avian myelocytomatosis viral oncogene homolog) and a subset of its regulated genes.