Co-localization of TAZ and H2A.Z up-regulates IL-6 expression in alveolar epithelial cells to polarize M2 cells to alleviate hypoxia-induced lung injury.

Transcriptional co-activator with PDZ-binding motif (TAZ) plays a critical role in the repair process following lung injury by enhancing the proliferation of alveolar epithelial cells (AECs) and exerting anti-inflammatory effects post-injury. Hypoxia is a significant factor in inducing lung injury. However, whether and how TAZ regulates transcription of target genes involved in hypoxia-induced lung injury remains unclear. In this study, we discovered that M2 macrophages protected against hypoxic condition-induced lung injury, coinciding with increased TAZ expression in hypoxic AECs. Experimental verification confirmed that the up-regulation of TAZ promoted AEC proliferation. Furthermore, we found that TAZ interacted with H2A.Z, a histone H2A variant. CUT&Tag sequencing verified that TAZ was essential for maintaining the enrichment of H2A.Z at the promoters of their shared target genes in hypoxic AECs. Gene Ontology analysis revealed a significant predominance of pathways associated with IL-6 mediation, indicating that this pathway is the most enriched in our dataset. Importantly, IL-6 secreted by AECs under hypoxia stimulates the polarization of macrophages towards the M2 phenotype, thereby promoting lung tissue repair after hypoxia exposure. In summary, our findings demonstrate that TAZ facilitates the deposition of H2A.Z at the IL-6 gene promoter, thereby enhancing IL-6 expression in hypoxic AECs. This, in turn, induces M2 macrophage polarization and PD-L1 expression, ultimately mitigating hypoxic condition-induced lung injury.