Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell death.
Junsong WuMuhammad Qasim BarkatJiakun SuFugen WuDan TanTingyu ShenQiangqiang HeMeiyu QuMeiping LuJibao CaiXimei WuChengyun XuPublished in: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (2023)
Infections like COVID-19 are the primary cause of death around the world because they can cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis. Inflammatory cells serve as crucial protective barriers in these diseases. However, excessive accumulation of inflammatory cells is also one of the major causes of organ damage. The non-muscular myosin light chain kinase (nmMLCK) plays crucial of cytoskeletal components involved in endothelial cell-matrix and cell-cell adhesion, integrity, and permeability. Our previous investigations found that ML-7, a specific inhibitor of MLCK, promoted neutrophil apoptosis through various signaling pathways. In this study, we found that knockout of MLCK significantly promote apoptosis of neutrophils and macrophages in the BALF of the LPS-induced ALI, meanwhile it had no effect on the apoptosis of neutrophils in the circulatory system. RNA-sequencing revealed that the effect of MLCK knockout in inducing apoptosis of inflammatory cells was mediated through lysosomes. Administering ML-7 into the lungs significantly promoted neutrophil apoptosis, accelerating their clearance. In the LPS- or CLP-induced sepsis models, ML-7 administration significantly improves the apoptosis of inflammatory cells, especially neutrophils, at the infection site but had no impact on neutrophils in the circulatory system. ML-7 also significantly improved the survival rate of mice with LPS- or CLP-induced sepsis. Taken together, we found that MLCK plays a crucial role in the survival of inflammatory cells at the infection site. Inhibiting MLCK significantly induces apoptosis of inflammatory cells at the infection site, promoting inflammation resolution, with no impact of the circulatory system.
Keyphrases
- cell cycle arrest
- cell death
- induced apoptosis
- oxidative stress
- endoplasmic reticulum stress
- pi k akt
- acute respiratory distress syndrome
- signaling pathway
- sars cov
- single cell
- intensive care unit
- diabetic rats
- extracorporeal membrane oxygenation
- stem cells
- type diabetes
- coronavirus disease
- inflammatory response
- mesenchymal stem cells
- lipopolysaccharide induced
- weight gain
- mechanical ventilation
- epithelial mesenchymal transition
- weight loss