Cmpk2 Protects Against Acute Lung Injury in Mice

Area of Science:

• Mitochondrial biology and metabolic enzymes
• Innate immunity and host defense mechanisms
• Respiratory diseases and acute lung injury

Background:

• Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are severe conditions characterized by hypoxemia and pulmonary edema, often involving mitochondrial dysfunction.
• Cytidine/uridine monophosphate kinase 2 (Cmpk2), a mitochondrial metabolic enzyme, is implicated in inflammation and senescence, but its specific role in ARDS pathogenesis is not well understood.

Purpose of the Study:

• To investigate the function of Cmpk2 in Pseudomonas aeruginosa-induced ALI using a global Cmpk2 knockout (KO) mouse model.
• To elucidate the molecular mechanisms underlying Cmpk2's protective effects in ALI and bacterial pneumonia.

Main Methods:

• Cmpk2 expression was analyzed in ARDS patient datasets.
• Murine ALI was induced by P. aeruginosa; lung pathology, leukocyte recruitment, and cytokine levels were assessed.
• Gene Ontology (GO) and KEGG pathway analyses were performed. Single-cell RNA sequencing (scRNA-seq) data from ARDS patients were used to analyze Cmpk2 expression in leukocytes. Neutrophil phagocytosis assays and zebrafish infection models were employed.

Main Results:

• Cmpk2 expression was significantly upregulated in ARDS patients.
• Cmpk2 KO mice exhibited exacerbated P. aeruginosa-induced ALI, with increased lung damage, permeability, inflammation, and neutrophil infiltration.
• Cmpk2 deficiency impaired neutrophil phagocytosis and reduced host survival, linked to decreased STING expression, which was reversible with a STING inhibitor.

Conclusions:

• Cmpk2 plays a protective role against pneumonia-induced ALI.
• Cmpk2 attenuates neutrophil recruitment and enhances bacterial phagocytosis through STING-dependent mechanisms.
• Targeting Cmpk2 may offer a therapeutic strategy for ARDS and bacterial pneumonia.