PGC-1α mediates migrasome secretion accelerating macrophage-myofibroblast transition and contributing to sepsis-associated pulmonary fibrosis.

Summary

Using LPS-induced models, the authors show that PGC-1α suppression in lung fibroblasts causes mitochondrial dysfunction and release of mtDNA-laden migrasomes, which trigger macrophage–myofibroblast transition and drive sepsis-associated pulmonary fibrosis. Restoring PGC-1α attenuated migrasome release, inhibited MMT, and alleviated fibrosis, revealing a targetable fibroblast–immune cell crosstalk.

Key Findings

• LPS suppressed PGC-1α in lung fibroblasts, inducing mitochondrial dysfunction and cytosolic mtDNA accumulation.
• Fibroblast stress promoted secretion of mtDNA-containing migrasomes that initiated macrophage–myofibroblast transition (MMT).
• Activation of PGC-1α reduced migrasome release, inhibited MMT, and alleviated sepsis-associated pulmonary fibrosis in vivo.

Clinical Implications

Although preclinical, the data suggest that enhancing PGC-1α or interrupting migrasome signaling could prevent or mitigate post-sepsis pulmonary fibrosis, potentially improving long-term outcomes after sepsis/ARDS.

Limitations

• Preclinical models; human validation in sepsis survivors with fibrosis is lacking.
• LPS-induced injury may not recapitulate all aspects of clinical SAPF heterogeneity.

Future Directions

Validate PGC-1α/migrasome signatures in human biospecimens post-sepsis, and test pharmacologic PGC-1α activators or migrasome pathway inhibitors in translational models.