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A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization.

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.

SUBMITTER: Li C

PROVIDER: S-EPMC10862067 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization.

Li Chunlu C Deng Chengsi C Wang Siwei S Dong Xiang X Dai Bing B Guo Wendong W Guo Qiqiang Q Feng Yanling Y Xu Hongde H Song Xiaoyu X Cao Liu L

Redox biology 20240201

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 phosphorylat ...[more]

PMID: 38316066

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Project description:Sepsis-induced acute lung injury (SALI) is characterized by a high incidence and mortality rate, which has caused a serious medical burden. The pharmacological effects of esculetin (ELT), such as antibacterial and anti-inflammatory actions, have been widely confirmed. However, the therapeutic effects and mechanisms of ELT on SALI still need to be further clarified. In this study, we first evaluated the therapeutic potential of ELT on a caecal ligation and puncture (CLP) induced septic rat model, particularly in the treatment of acute lung injury. Afterwards, we explored the effect of ELT on macrophage polarization in vivo and in vitro. Then, we investigated the anti-inflammatory mechanism of ELT based on modulating the metabolic reprogramming of macrophage (the effect on glycolysis in M1, and the effect on fatty acid β-oxidation in M2). In addition, macrophage metabolic inhibitors (glycolysis inhibitor: 2-DG, and fatty acid β-oxidation inhibitor: etomoxir) were used to verify the regulatory effect of ELT on macrophage metabolic reprogramming. Our results proved that ELT intervention could effectively improve the survival rate of SALI rats and ameliorate pathological injury. Next, we found that ELT intervention inhibited M1 polarization and promoted M2 polarization of macrophages in vivo and in vitro, including the downregulation of M1-related markers (CD86, iNOS), the decrease of pro-inflammatory factors (nitric oxide, IL-1β, IL-6, and TNF-α), the upregulation of M2-related markers (CD206, ARG-1), the increase of immunomodulatory factors (IL-4 and IL-10). Subsequently, seahorse analysis showed that ELT intervention inhibited the glycolytic capacity in M1, and promoted the ability of fatty acid β-oxidation in M2. Besides, ELT intervention inhibited the level of glycolysis product (lactic acid), and the expression of glycolysis-related genes (Glut1, Hk2, Pfkfb1, Pkm and Ldha) and promoted the expression of fatty acid β-oxidation related genes (Cpt1a, Cpt2, Acox1). In addition, we found that the inhibitory effect of ELT on M1 polarization was comparable to that of 2-DG, while intervention with etomoxir abolished the promoting effect of ELT on M2 polarization. ELT inhibited the inflammatory response in SALI by correcting macrophage polarization (inhibiting M1 and promoting M2). The mechanism of ELT on macrophage polarization was associated with regulating metabolic reprogramming (inhibiting glycolysis in M1 and promoting fatty acid β-oxidation in M2).

Dataset Information

A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization.

Publications

A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization.

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