Extracellular AMP Suppresses Endotoxemia-Induced Inflammation by Alleviating Neutrophil Activation

Area of Science:

• Biochemistry
• Immunology
• Cell Biology

Background:

• Intracellular adenosine monophosphate (AMP) is vital for cellular energy metabolism and signaling.
• The biological role of extracellular AMP, particularly in inflammatory conditions, remains largely undefined.

Purpose of the Study:

• To investigate the function of extracellular AMP in endotoxemia.
• To elucidate the mechanism by which extracellular AMP modulates inflammation and neutrophil activity.

Main Methods:

• Utilized in vivo and in vitro models of lipopolysaccharide (LPS)-induced endotoxemia.
• Employed adenosine 1 receptor (A1R) antagonists and inhibitors of AMP to adenosine conversion.
• Analyzed neutrophil functions, including reactive oxygen species (ROS) production, degranulation, and cytokine release.
• Investigated the involvement of the p38 mitogen-activated protein kinase (MAPK) signaling pathway.
• Examined serum samples from septic patients and healthy volunteers.

Main Results:

• Extracellular AMP significantly inhibited inflammation and neutrophil activation in LPS-induced endotoxemia.
• The anti-inflammatory effects of AMP were mediated by direct activation of the adenosine 1 receptor (A1R), independent of conversion to adenosine.
• AMP suppressed LPS-induced ROS production, degranulation, and cytokine release in neutrophils.
• AMP's regulation of neutrophil function involved the inhibition of the p38 MAPK pathway.
• Elevated serum AMP levels were observed in septic patients, negatively correlating with disease severity.

Conclusions:

• Extracellular AMP acts as an endogenous anti-inflammatory agent by activating A1R and suppressing neutrophil overactivation during endotoxemia.
• The p38 MAPK pathway is a key mediator of extracellular AMP's inhibitory effects on neutrophil function.
• Increased extracellular AMP levels in sepsis may represent a protective host response.