Meis1-driven suppression of MIF/CD74 signaling promotes M2 macrophage polarization and protects against inflammatory damage in experimental acute lung injury.

Abstract

Acute lung injury (ALI) is marked by dysregulated inflammatory responses, disruption of the alveolar-capillary barrier, and defective tissue repair, in which macrophages function both as drivers of tissue damage and facilitators of resolution. Here, we explored the transcriptional regulation of macrophage polarization in ALI using integrative single-cell and bulk RNA sequencing approaches. Meis1 was identified as a critical transcriptional factor that promotes macrophage skewing toward the M2 phenotype, associated with anti-inflammatory and reparative functions. Mechanistic dissection revealed that Meis1 negatively regulates the MIF/CD74 signaling pathway, thereby limiting pro-inflammatory macrophage activity. Experimental validation in vitro confirmed that Meis1 enhances expression of M2-associated markers while suppressing inflammatory cytokine release. In vivo studies using a murine ALI model demonstrated that Meis1 overexpression alleviates lung inflammation, reduces tissue damage, and accelerates structural repair. These findings establish Meis1 as a key modulator of immune cell fate in injured lungs. Through inhibition of MIF/CD74 signaling, Meis1 constrains inflammatory toxicity and supports tissue repair, revealing a novel regulatory pathway that may be exploited for treating ALI and related inflammatory lung conditions.