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

Abstract

Bronchopulmonary dysplasia is a common complication of preterm birth, driven in part by the inflammatory effects of supplemental oxygen on the immature lung. Although oxygen therapy is essential, it contributes to disrupted lung development but not all infants are equally susceptible. Using genetically diverse mouse models, we found that hyperoxia-sensitive mice exhibit a distinct innate immune response compared to resilient strains. Notably, the hyperoxia-sensitive C57BL/6J strain showed selective upregulation of TREM2 on lung macrophages and monocytes. Deletion of TREM2 in myeloid cells led to reduced inflammation, preserved alveolar structure and sustained cell proliferation in the developing lung following oxygen exposure. Mechanistically, TREM2 loss limited p53 activation, favoring cell-cycle arrest over apoptosis. These results identify TREM2 as a key driver of immune-mediated lung injury in neonatal hyperoxia and suggest it may be a promising therapeutic target for preventing or treating bronchopulmonary dysplasia in vulnerable preterm infants.