Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor, majorly expressed by granulocytes, monocytes and macrophages. We in this study showed that TREM2 was downregulated in the lipopolysaccharide (LPS)-treated macrophages and murine acute lung injury (ALI) through activation of p38 MAPK and STAT6 signaling. Over-expression of TREM2 reduced the expression of DNAX-activation protein 12 (DAP12), pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), Malondialdehyde (MDA) and hemosiderin accumulation in LPS-treated macrophages. Knockdown of TREM2 expression elevated the expression of IL-6, reactive oxygen species (ROS), lactate dehydrogenases (LDH) and hemosiderin accumulation. Intratracheal adoptive transfer of TREM2-overexpressing macrophages effectively suppressed the lung inflammation and pro-inflammatory cytokine expression in murine ALI. While downregulation of TREM2 enhanced the lung inflammation in the lung tissues of murine ALI. Therefore, TREM2/DAP12 axis is involved in macrophage ferroptosis and attenuation of murine ALI. TREM2 would be a novel therapeutic target in murine ALI and patients with acute respiratory distress syndrome (ARDS).