5-HT promotes bronchopulmonary dysplasia via TGM2-mediated serotonylation

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in preterm neonates. Untargeted metabolomics of serum samples revealed that tryptophan metabolism may be involved in the pathogenesis of BPD. Specifically, the serum level of 5-hydroxytryptamine (5-HT), a metabolite of tryptophan, is increased in preterm infants with BPD. Similarly, the pulmonary level of 5-HT is increased in a mouse model of hyperoxia-induced BPD. Administration of 5-HT directly impaired lung maturation. Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme in the biosynthesis of 5-HT. As expected, the TPH1 inhibitor LP533401 mitigated lung injury in pups exposed to 85% oxygen. Mechanistically, 5-HT promotes post-translational serotonylation via transglutaminase 2 (TGM2) in alveolar epithelial cells. TGM2 expression is increased in the pulmonary tissues of BPD-like mice. Blocking TGM2 partially reversed BPD-like damage to the lungs. Collectively, our findings highlight the roles of 5-HT and serotonylation in the pathogenesis of BPD.