Geranylgeranyl diphosphate synthase deficiency impairs efferocytosis and resolution of acute lung injury.

Summary

Using myeloid-specific GGPPS knockout models, the study shows that loss of GGPPS impairs AXL-dependent efferocytosis in recruited macrophages, prolonging lung inflammation and delaying resolution of acute lung injury. Geranylgeraniol restored efferocytosis and AXL expression, positioning the isoprenoid pathway as a modifiable target to accelerate ARDS resolution.

Key Findings

• GGPPS expression dynamically changes in lung macrophages and circulating monocytes across ALI progression and resolution.
• Myeloid-specific GGPPS knockout prolongs lung inflammation, increases apoptotic neutrophil accumulation, raises recruited macrophages, and reduces resident macrophages.
• Recruited macrophages dominate efferocytosis; GGPPS deficiency suppresses efferocytosis in both recruited and resident subsets in vivo and in vitro.
• GGPPS knockout disrupts AXL signaling in recruited macrophages, and geranylgeraniol restores efferocytosis and AXL expression, rescuing delayed resolution.

Clinical Implications

While preclinical, targeting the isoprenoid pathway (e.g., augmenting GGPPS activity or AXL signaling) could enhance efferocytosis and hasten resolution in ARDS. Translational studies in human ARDS macrophages and early-phase trials of pathway modulators are warranted.

Limitations

• Preclinical animal study; human validation and clinical translatability remain to be established
• Dosing, safety, and efficacy of pathway modulation (e.g., GGOH) in humans are unknown

Future Directions

Validate the GGPPS–AXL axis in human ARDS macrophages, define recruited vs resident macrophage targeting strategies, and test small-molecule or gene-based modulators in translational models and early-phase trials.