Critical Role of IL1R2-ENO1 Interaction in Inhibiting Glycolysis-Mediated Pyroptosis for Protection Against Lethal...

Area of Science:

• Immunology
• Cell Metabolism
• Molecular Biology

Background:

• Immune cell metabolic reprogramming, particularly glycolysis, is crucial for sepsis defense.
• The role of interleukin 1 receptor 2 (IL1R2) in sepsis-related cell metabolism and death is not well understood.
• Elevated plasma soluble IL1R2 (sIL1R2) levels were observed in septic patients and mice.

Purpose of the Study:

• To investigate the function of IL1R2 in sepsis.
• To identify IL1R2's molecular interactions and their impact on immune cell metabolism and death.
• To evaluate the therapeutic potential of targeting the IL1R2-ENO1 pathway in sepsis.

Main Methods:

• Measurement of sIL1R2 levels in septic patients and mice.
• Analysis of intracellular IL1R2 expression in pyroptotic macrophages.
• Proteomic screening to identify IL1R2 binding partners in macrophages.
• Assessment of IL1R2's effect on glycolysis, pyroptosis (GSDMD-mediated), and inflammation.
• Evaluation of IL1R2-deficient mice and ENO1 inhibition in a sepsis model.

Main Results:

• Reduced intracellular IL1R2 expression correlated with extracellular release in pyroptotic macrophages.
• Enolase 1 (ENO1), a glycolysis enzyme, was identified as an IL1R2 binding partner.
• IL1R2 binding to ENO1 suppressed glycolysis, GSDMD-mediated pyroptosis, and inflammation.
• IL1R2-deficient mice showed increased sepsis susceptibility, inflammation, organ injury, and mortality.
• ENO1 inhibition ameliorated sepsis-induced inflammation, organ injury, and improved survival.

Conclusions:

• IL1R2 interacts with ENO1 to inhibit glycolysis-driven pyroptosis and inflammation during sepsis.
• The IL1R2-ENO1 pathway represents a novel therapeutic target for sepsis management.