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Updated: Jun 5, 2025
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
M2 macrophages secrete CCL20 to regulate iron metabolism and promote daunorubicin resistance in AML cells
Zhi-Gang Chen1, Yu-Tong Xie1, Chao Yang1
1Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China 400037.
Abstract:
Chemotherapy resistance is a significant clinical challenge in the treatment of leukemia. M2 macrophages have been identified as key contributors to the development of chemotherapy resistance in cancer, yet the precise mechanisms by which macrophages regulate this resistance remain elusive. Our study has identified CCL20 as a pivotal factor in the promotion of chemoresistance in AML cells by M2 macrophages. The chemotherapeutic agent daunorubicin induces a marked increase in ROS and lipid peroxidation levels within AML cells. This is accompanied by the inhibition of the SLC7A11/GCL/GPX4 signaling axis, elevated levels of intracellular free iron, disrupted iron metabolism, and consequent mitochondrial damage, ultimately leading to ferroptosis. Notably, CCL20 enhances the ability of AML cells to maintain iron homeostasis by upregulating SLC7A11 protein activity, mitigating mitochondrial damage, and inhibiting ferroptosis, thereby contributing to chemotherapy resistance. Furthermore, in vivo experiments demonstrated that blocking CCL20 effectively restores the sensitivity of AML cells to daunorubicin chemotherapy. Collectively, these findings underscore the complex interplay between M2 macrophages, CCL20 signaling, and chemotherapy resistance in AML, highlighting potential therapeutic avenues for intervention.
Insights
M2 macrophages promote chemotherapy resistance in acute myeloid leukemia (AML) by secreting CCL20. This molecule inhibits ferroptosis in AML cells, offering a target to restore drug sensitivity and improve leukemia treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Chemotherapy resistance is a major obstacle in treating acute myeloid leukemia (AML).
- M2 macrophages are implicated in cancer chemoresistance, but their exact mechanisms are unclear.
- Understanding macrophage-mediated chemoresistance is crucial for developing effective leukemia therapies.
Purpose of the Study:
- To elucidate the role of M2 macrophages and CCL20 in daunorubicin resistance in AML.
- To investigate the molecular mechanisms linking M2 macrophages, CCL20, and ferroptosis in AML cells.
- To evaluate the therapeutic potential of targeting CCL20 in AML.
Main Methods:
- Analysis of ROS, lipid peroxidation, and iron metabolism in AML cells treated with daunorubicin.
- Investigation of the SLC7A11/GCL/GPX4 signaling axis and its regulation by CCL20.
- In vivo studies using animal models to assess the efficacy of CCL20 blockade.
Main Results:
- Daunorubicin treatment induced ferroptosis in AML cells by increasing ROS, lipid peroxidation, and inhibiting the SLC7A11/GCL/GPX4 axis.
- CCL20 secreted by M2 macrophages protected AML cells from ferroptosis by upregulating SLC7A11 activity, preserving iron homeostasis and mitochondrial function.
- Blocking CCL20 in vivo restored AML cell sensitivity to daunorubicin chemotherapy.
Conclusions:
- CCL20 is a key mediator by which M2 macrophages confer chemoresistance in AML.
- CCL20 protects AML cells from ferroptosis, contributing to treatment failure.
- Targeting the CCL20-mediated pathway presents a promising strategy to overcome chemotherapy resistance in AML.
