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

Redox Biol. 2024 Apr:70:103059. doi: 10.1016/j.redox.2024.103059. Epub 2024 Feb 1.


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.

Keywords: Chk2; Macrophage; PKM2; ROS; p21.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Ataxia Telangiectasia*
  • Cell Cycle
  • Cell Cycle Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • Inflammation
  • Macrophages / metabolism
  • Mice
  • Phosphorylation
  • Protein Serine-Threonine Kinases* / metabolism
  • Reactive Oxygen Species / metabolism
  • Tumor Suppressor Proteins / metabolism


  • Protein Serine-Threonine Kinases
  • Cell Cycle Proteins
  • Reactive Oxygen Species
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • DNA-Binding Proteins