HIF-1α Promotes Macrophage Extracellular Trap Formation and Exacerbates Acute Lung Injury in Neonatal Sepsis

Area of Science:

• Immunology
• Neonatal Research
• Pulmonology

Background:

• Neonatal sepsis causes acute lung injury (ALI), a significant mortality factor.
• Mechanisms of early lung damage and the role of extracellular traps (ETs) in neonatal sepsis are unclear.
• The cellular origin and regulation of ET formation in neonatal sepsis require investigation.

Purpose of the Study:

• Identify the cellular source of ETs in neonatal sepsis.
• Investigate the role of hypoxia-inducible factor-1α (HIF-1α) in regulating macrophage extracellular traps (METs) formation.
• Determine the therapeutic potential of targeting HIF-1α in neonatal sepsis-associated ALI.

Main Methods:

• Induced neonatal sepsis in mice via cecal slurry injection.
• Assessed METs formation using immunofluorescence, Western blotting, and DNA quantification.
• Utilized macrophage depletion, in vitro stimulation, RNA sequencing, and pharmacological inhibition to study METs and HIF-1α pathways.

Main Results:

• Macrophages are a primary source of ETs in the neonatal sepsis lung.
• METs contribute to lung injury; macrophage depletion or METs inhibition improved survival.
• HIF-1α promotes METs formation by enhancing glycolysis and upregulating enzymes like ENO2 in macrophages.
• Targeting HIF-1α reduced METs, inflammation, and improved survival outcomes.

Conclusions:

• Macrophages play a key role in neonatal sepsis-associated ALI through METs formation.
• HIF-1α is a critical regulator of METs production in this context.
• Targeting the HIF-1α pathway presents a promising therapeutic strategy for neonatal sepsis-associated ALI.