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Updated: Jul 31, 2025
Macrophage Differentiation and Polarization into an M2-Like Phenotype using a Human Monocyte-Like THP-1 Leukemia Cell Line
Published on: August 2, 2021
MTHFD2 reprograms macrophage polarization by inhibiting PTEN.
Man Shang1, Lina Ni1, Xiao Shan1
1Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China.
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) regulates macrophage polarization by interacting with PTEN, influencing immune responses. This enzyme suppresses M(IFN-γ) and enhances M(IL-4) polarization through non-metabolic functions.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a one-carbon metabolism enzyme implicated in tumor oncogenesis and immune cell regulation.
- The precise role of MTHFD2 in modulating macrophage polarization, a critical process in immune responses, remains largely unexplored.
Purpose of the Study:
- To investigate the role of MTHFD2 in regulating macrophage polarization.
- To elucidate the molecular mechanisms underlying MTHFD2's function in macrophage polarization.
Main Methods:
- In vitro and in vivo experiments assessing macrophage polarization.
- Co-immunoprecipitation assays to study protein-protein interactions.
- Analysis of enzyme activity and downstream signaling pathways (e.g., Akt activation).
Main Results:
- MTHFD2 suppresses interferon-γ-activated macrophage (M(IFN-γ)) polarization while enhancing interleukin-4-activated macrophage (M(IL-4)) polarization.
- MTHFD2 interacts with phosphatase and tensin homolog (PTEN), inhibiting its phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase activity and promoting Akt activation.
- The MTHFD2-PTEN interaction is IL-4 dependent and involves specific amino acid residues in both proteins, highlighting a non-metabolic function of MTHFD2.
Conclusions:
- MTHFD2 plays a critical role in orchestrating macrophage polarization through a non-metabolic interaction with PTEN.
- This interaction modulates PTEN activity, influencing downstream signaling and ultimately altering macrophage-mediated immune responses.
- Findings reveal a novel regulatory mechanism of macrophage polarization by MTHFD2, with implications for immune cell function and disease.
