PFKFB2-Driven Glycolysis Promotes Dendritic Cell Maturation and Exacerbates Acute Lung Injury

Area of Science:

• Immunology
• Cell Biology
• Respiratory Medicine

Background:

• Acute lung injury (ALI) involves complex immune dysregulation.
• Dendritic cells (DCs) are key immune regulators, but their precise role in ALI pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of the hypoxia-inducible factor-1α (HIF-1α) and its target gene, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), in dendritic cell (DC) maturation and ALI.

Main Methods:

• Investigated HIF-1α binding to the PFKFB2 promoter.
• Utilized mouse models of paraquat (PQ)-induced ALI and lipopolysaccharide (LPS)-induced ALI.
• Employed DC-specific PFKFB2 knockout mice and nanoparticle-mediated delivery of HIF-1α inhibitors.
• Analyzed human lung tissues from ALI patients (PQ poisoning, bacterial pneumonia, COVID-19) and controls.

Main Results:

• HIF-1α directly upregulates PFKFB2, increasing glycolysis and promoting DC maturation.
• DC-specific PFKFB2 knockout or HIF-1α inhibition significantly reduced DC maturation and ALI severity in mouse models.
• Increased PFKFB2 expression and DC maturation were observed in human ALI lung tissues.

Conclusions:

• The HIF-1α-PFKFB2 signaling pathway is a critical driver of glycolysis-dependent DC maturation and immune activation in ALI.
• This pathway represents a potential therapeutic target for managing acute lung injury.