Genetic variation in the activity of a TREM2-p53 signaling axis determines oxygen-induced lung injury

Area of Science:

• Neonatal medicine
• Immunology
• Pulmonary biology

Background:

• Bronchopulmonary dysplasia (BPD) is a frequent complication in preterm infants, exacerbated by supplemental oxygen's inflammatory impact on immature lungs.
• While oxygen is vital, its use can impair lung development, with varying susceptibility among infants.

Purpose of the Study:

• To investigate the distinct innate immune responses in hyperoxia-sensitive versus resilient mouse models of neonatal lung injury.
• To identify specific molecular pathways contributing to oxygen-induced lung damage in the context of BPD.

Main Methods:

• Utilized genetically diverse mouse models exposed to hyperoxia (excess oxygen).
• Analyzed immune cell populations, focusing on TREM2 expression in lung macrophages and monocytes.
• Generated myeloid-specific TREM2 knockout mice to assess its functional role in oxygen-induced lung injury.
• Evaluated lung inflammation, alveolar structure, cell proliferation, and p53/apoptosis pathways.

Main Results:

• Hyperoxia-sensitive mice (C57BL/6J) exhibited TREM2 upregulation on lung myeloid cells.
• TREM2 deletion in myeloid cells significantly reduced inflammation and preserved lung alveolar structure and cell proliferation post-oxygen exposure.
• Loss of TREM2 attenuated p53 activation, promoting cell-cycle arrest over apoptosis.

Conclusions:

• TREM2 is identified as a critical mediator of immune-driven lung injury during neonatal hyperoxia.
• Targeting TREM2 presents a potential therapeutic strategy for mitigating lung damage and preventing BPD in susceptible preterm infants.