Divergent effects of MIF on lung alveolar repair

Abstract

Emphysema is an important phenotype of chronic obstructive pulmonary disease (COPD) characterized by alveolar destruction. Macrophage migration inhibitory factor (MIF)-deficient mice develop spontaneous emphysema and MIF, through one of its receptors CD74, was shown to induce type II alveolar epithelial cell proliferation in vitro. However, how MIF and through which of its receptors, is involved in alveolar repair in COPD and healthy conditions has not been elucidated yet. Therefore, we aimed to investigate the effects of MIF on lung alveolar repair using a model of lung organoids established by co-culturing fibroblasts with primary EpCAM+ cells, isolated from lung tissue of healthy mice or patients with or without COPD. MIF treatment of EpCAM+ cells from healthy mice resulted in significantly fewer alveolar organoids compared to untreated controls. A similar trend was found for human organoids derived from patients without COPD or COPD GOLD I. However, MIF treatment of EpCAM+ cells from severe COPD patients (GOLD III/IV) induced more and larger alveolar organoids compared to controls. This divergence may suggest differential expression of MIF receptors in severe COPD and we therefore investigated expression of CD74, CXCR2, CXCR4, and CXCR7 in a lung tissue RNA-sequencing dataset of control vs COPD GOLD IV patients. CXCR4 gene expression was significantly higher in severe COPD, whereas other MIF receptors were not differentially expressed. In conclusion, MIF only promoted alveolar organoid formation and growth in cells isolated from severe COPD lungs. As CXCR4 was shown to regulate migration of lung alveolar epithelial cells before, its higher expression in severe COPD may explain this divergent effect of MIF on lung alveolar repair.