LAMP2-FLOT2 interaction enhances autophagosome-lysosome fusion to protect the septic heart in response to ILC2.

Summary

In CLP-induced sepsis, ILC2s expand and their IL-4 restores impaired autophagic flux via STAT3-driven LAMP2 upregulation. IL-4 promotes a LAMP2–FLOT2 interaction that enhances autophagosome-lysosome fusion in cardiac endothelial cells, reducing inflammation and improving cardiac function. Loss of FLOT2 abrogates these protective effects.

Key Findings

• ILC2s expand in the septic heart and their IL-4 attenuates cardiac inflammation and improves function in CLP sepsis.
• IL-4 activates STAT3 to upregulate LAMP2, stabilizing lysosomal homeostasis and rescuing impaired autophagic flux.
• LAMP2 preferentially binds FLOT2 after IL-4 exposure, enhancing autophagosome-lysosome fusion in cardiac endothelial cells.
• FLOT2 loss reverses IL-4/LAMP2-mediated autophagy regulation, leading to autophagosome accumulation.

Clinical Implications

Although preclinical, these findings suggest that enhancing IL-4 signaling or stabilizing LAMP2–FLOT2 interaction to restore autophagic flux may offer a novel strategy to prevent or treat septic cardiomyopathy.

Limitations

• Preclinical animal study without human tissue or clinical validation.
• Therapeutic translatability of IL-4 delivery or LAMP2–FLOT2 modulation is untested in vivo in large animals or humans.

Future Directions

Validate the IL-4–LAMP2–FLOT2 axis in human septic myocardium; develop small molecules or biologics to enhance LAMP2–FLOT2 interaction; assess safety and efficacy in translational models.