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Published on: November 28, 2015
A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage
Chunlu Li1, Chengsi Deng1, Siwei Wang1
1The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province, China.
Abstract:
Reactive oxygen species (ROS) play a pivotal role in macrophage-mediated acute inflammation. However, the precise molecular mechanism by which ROS regulate macrophage polarization remains unclear. Here, we show that ROS function as signaling molecules that regulate M1 macrophage polarization through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (Chk2), vital effector kinases in the DNA damage response (DDR) signaling pathway. We further demonstrate that Chk2 phosphorylates PKM2 at the T95 and T195 sites, promoting glycolysis and facilitating macrophage M1 polarization. In addition, Chk2 activation increases the Chk2-dependent expression of p21, inducing cell cycle arrest for subsequent macrophage M1 polarization. Finally, Chk2-deficient mice infected with lipopolysaccharides (LPS) display a significant decrease in lung inflammation and M1 macrophage counts. Taken together, these results suggest that inhibiting the ROS-Chk2 axis can prevent the excessive inflammatory activation of macrophages, and this pathway can be targeted to develop a novel therapy for inflammation-associated diseases and expand our understanding of the pathophysiological functions of DDR in innate immunity.
Insights
Reactive oxygen species (ROS) signal M1 macrophage polarization via DNA damage response (DDR) kinases ATM and Chk2. Inhibiting this ROS-Chk2 pathway reduces lung inflammation, offering a potential therapy for inflammatory diseases.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Reactive oxygen species (ROS) are critical in macrophage-mediated inflammation.
- The exact molecular mechanisms linking ROS to macrophage polarization are not fully understood.
Purpose of the Study:
- To elucidate the role of ROS in regulating macrophage polarization.
- To identify the specific molecular pathways involved in ROS-mediated M1 macrophage polarization.
Main Methods:
- Investigated the signaling pathway involving ROS, ATM, and Chk2 in macrophage polarization.
- Utilized molecular assays to determine Chk2 phosphorylation of PKM2 and its effect on glycolysis.
- Examined the impact of Chk2 on p21 expression and cell cycle arrest.
- Assessed lung inflammation and M1 macrophage counts in Chk2-deficient mice infected with LPS.
Main Results:
- ROS act as signaling molecules regulating M1 macrophage polarization through ATM and Chk2 kinases.
- Chk2 phosphorylates PKM2, enhancing glycolysis and promoting M1 polarization.
- Chk2 activation upregulates p21, inducing cell cycle arrest essential for M1 polarization.
- Chk2-deficient mice showed reduced lung inflammation and M1 macrophage numbers upon LPS challenge.
Conclusions:
- The ROS-Chk2 axis is a key regulator of M1 macrophage polarization.
- Targeting the ROS-Chk2 pathway offers a potential therapeutic strategy for inflammatory diseases.
- This study expands the understanding of DNA damage response (DDR) in innate immunity.
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