Related Experiment Video
Updated: Apr 19, 2026
Macrophage Differentiation and Polarization into an M2-Like Phenotype using a Human Monocyte-Like THP-1 Leukemia Cell Line
Published on: August 2, 2021
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.
Insights
The tumor suppressor p53 acts as a brake on M2 macrophage polarization by downregulating M2 genes via the p53/MDM2/c-MYC axis. This reveals a new role for p53 in inflammation and macrophage plasticity.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- The tumor suppressor p53 is crucial for preventing cancer.
- The role of p53 in inflammation and macrophage function remains unclear.
- Macrophages exhibit plasticity, with subtypes like M2 macrophages involved in tissue repair and immune suppression.
Purpose of the Study:
- To investigate the role of p53 in macrophage polarization, specifically in M2 macrophages.
- To elucidate the molecular mechanisms by which p53 influences M2 macrophage function.
- To explore the potential impact of p53 modulation on inflammatory responses.
Main Methods:
- Utilized bone marrow-derived macrophages (BMDMs) and peritoneal macrophages from mice.
- Employing p53-deficient and p53 mutant mice models.
- Stimulation with interleukin-4 (IL-4) to induce M2 polarization.
- Treatment with Nutlin-3a to activate p53.
- Assessed gene expression of M2 markers and c-Myc.
- Investigated p53 binding to the c-Myc promoter.
Main Results:
- Endogenous p53 activity was detected in macrophages and increased upon M2 polarization.
- p53 activation, induced by Nutlin-3a or inherent in M2 polarization, reduced M2 gene expression.
- p53 deficiency or mutation led to increased M2 gene expression.
- p53 directly repressed c-Myc expression by binding to its promoter.
- Nutlin-3a treatment delayed the development of tolerance to lipopolysaccharide (LPS) in mice.
Conclusions:
- The p53/MDM2/c-MYC axis acts as a physiological brake on M2 macrophage polarization.
- p53 plays a previously unrecognized role in regulating macrophage plasticity and inflammatory responses.
- p53-activating drugs may have significant, potentially unforeseen, effects on macrophage function and immune responses.
More Related Videos
Related Concept Videos
02:23Abnormal Proliferation
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...