Abe Yohei, Spann Nathanael J, Tang Wenxi, Zeng Fenghua, Seymour Cadence, Jansky Sean, Guo Jason L, Huff Robert, Chanthavixay Kelly, Richard John Lalith Charles, Mooney Miguel, Dhar Debanjan, Ganguly Souradipta, Lopez David M, Longaker Michael T, Benner Christopher, Glass Christopher K, Sajti Eniko
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
Nat Immunol. 2025 Jul 25. doi: 10.1038/s41590-025-02217-4.
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.
支气管肺发育不良是早产的常见并发症，部分原因是补充氧气对未成熟肺的炎症作用。尽管氧疗至关重要，但它会导致肺发育中断，不过并非所有婴儿都同样易感。利用基因多样化的小鼠模型，我们发现与具有耐受性的品系相比，对高氧敏感的小鼠表现出独特的固有免疫反应。值得注意的是，对高氧敏感的C57BL/6J品系在肺巨噬细胞和单核细胞上显示出TREM2的选择性上调。髓系细胞中TREM2的缺失导致炎症减轻、肺泡结构得以保留以及在氧气暴露后发育中的肺中细胞增殖持续。从机制上讲，TREM2的缺失限制了p53的激活，有利于细胞周期停滞而非细胞凋亡。这些结果确定TREM2是新生儿高氧血症中免疫介导的肺损伤的关键驱动因素，并表明它可能是预防或治疗易患支气管肺发育不良的早产婴儿的有前景的治疗靶点。
