TREM2 protects against LPS-induced murine acute lung injury through suppressing macrophage ferroptosis.

Summary

TREM2 expression falls in LPS-induced ALI, and augmenting TREM2 in macrophages dampens cytokines, oxidative stress, and iron-related injury while adoptive transfer reduces lung inflammation. Data implicate the TREM2/DAP12 axis in restraining macrophage ferroptosis, positioning TREM2 as a therapeutic target.

Key Findings

• TREM2 is downregulated in LPS-treated macrophages and murine ALI via p38 MAPK and STAT6 activation.
• TREM2 overexpression reduces DAP12, pro-inflammatory cytokines, MDA, and hemosiderin accumulation; knockdown increases IL-6, ROS, LDH, and hemosiderin.
• Adoptive transfer of TREM2-overexpressing macrophages suppresses lung inflammation in murine ALI, implicating TREM2/DAP12 in restraining macrophage ferroptosis.

Clinical Implications

While preclinical, targeting TREM2 signaling or ferroptosis pathways may complement lung-protective ventilation in ARDS; macrophage-based therapies warrant exploration.

Limitations

• Murine LPS-induced ALI model may not fully recapitulate human ARDS pathophysiology
• Sample sizes and long-term outcomes were not detailed; no human validation

Future Directions

Dissect upstream regulators of TREM2 in ARDS, test pharmacologic TREM2 agonism or ferroptosis inhibitors, and validate in human macrophages and clinical biospecimens.