Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury
Maor Sauler1, Yi Zhang1, Jin-Na Min1
1Sections of *Pulmonary, Critical Care & Sleep Medicine and Rheumatology, Yale School of Medicine, and Department of Chemistry, Yale University, New Haven, Connecticut, USA.
Abstract:
Exposure to hyperoxia results in acute lung injury. A pathogenic consequence of hyperoxia is endothelial injury. Macrophage migration inhibitory factor (MIF) has a cytoprotective effect on lung endothelial cells; however, the mechanism is uncertain. We postulate that the MIF receptor CD74 mediates this protective effect. Using adult wild-type (WT), MIF-deficient (Mif(-/-)), CD74-deficient (Cd74(-/-)) mice and MIF receptor inhibitor treated mice, we report that MIF deficiency or inhibition of MIF receptor binding results in increased sensitivity to hyperoxia. Mif(-/-) and Cd74(-/-) mice demonstrated decreased median survival following hyperoxia compared to WT mice. Mif(-/-) mice demonstrated an increase in bronchoalveolar protein (48%) and lactate dehydrogenase (LDH) (68%) following 72 hours of hyperoxia. Similarly, treatment with MIF receptor antagonist resulted in a 59% and 91% increase in bronchoalveolar lavage protein and LDH, respectively. Inhibition of CD74 in primary murine lung endothelial cells (MLECs) abrogated the protective effect of MIF, including decreased hyperoxia-mediated AKT phosphorylation and a 20% reduction in the antiapoptotic effect of exogenous MIF. Treatment with MIF decreased hyperoxia-mediated H2AX phosphorylation in a CD74-dependent manner. These data suggest that therapeutic manipulation of the MIF-CD74 axis in lung endothelial cells may be a novel approach to protect against acute oxidative stress.
Insights
Macrophage migration inhibitory factor (MIF) protects lung endothelial cells from hyperoxia injury via its receptor CD74. Targeting the MIF-CD74 pathway may offer novel treatments for acute lung injury.
Area of Science:
- Cell Biology
- Immunology
- Pulmonary Medicine
Background:
- Hyperoxia exposure causes acute lung injury, characterized by endothelial cell damage.
- Macrophage migration inhibitory factor (MIF) exhibits protective effects on lung endothelial cells, but the underlying mechanism remains unclear.
Purpose of the Study:
- To investigate the role of the MIF receptor, CD74, in mediating the protective effects of MIF against hyperoxia-induced lung injury.
- To explore the therapeutic potential of targeting the MIF-CD74 axis for acute oxidative stress.
Main Methods:
- Utilized wild-type, MIF-deficient, and CD74-deficient mice models exposed to hyperoxia.
- Administered MIF receptor inhibitors to assess their impact on hyperoxia sensitivity.
- Examined primary murine lung endothelial cells (MLECs) to evaluate MIF's protective mechanisms, including effects on AKT and H2AX phosphorylation.
Main Results:
- MIF deficiency or CD74 deficiency significantly reduced median survival following hyperoxia exposure.
- MIF receptor inhibition increased bronchoalveolar lavage protein and lactate dehydrogenase levels, indicating enhanced lung injury.
- Inhibition of CD74 in MLECs abolished MIF's protective effects, including reduced AKT phosphorylation and anti-apoptotic benefits.
Conclusions:
- The MIF receptor CD74 is crucial for mediating the cytoprotective effects of MIF on lung endothelial cells during hyperoxia.
- Therapeutic strategies targeting the MIF-CD74 axis show promise for protecting against acute oxidative stress and lung injury.
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