Role of MIF and CD74 in the pathogenesis of emphysema

PROJECT SUMMARY
Emphysema is a common pathologic manifestation of Chronic Obstructive Pulmonary Disease (COPD), the
fourth leading cause of death in the United States. The most important modifiable risk factor for emphysema is
chronic exposure to cigarette smoke (CS). Yet, not all smokers develop emphysema and, therefore, cellular
responses to CS are important mechanisms underlying disease progression. Our long-term goal is to define
the cellular responses to CS and oxidative stress that protect the lung from emphysema. We have identified a
cytoprotective role for the innate immune cytokine Macrophage Migration Inhibitory (MIF). MIF decreases
oxidative stress and consequences of oxidative stress (e.g. cellular senescence and apoptosis) in lung
endothelial cells, and mice with a genetic deletion of Mif are susceptible to emphysema. MIF is secreted in
response to CS, but, paradoxically, MIF is decreased in patients with severe COPD. Targeting MIF, or its
downstream pathways, may be therapeutic. However, MIF is a pleiotropic molecule with broad regulatory effects.
To translate MIF biology into therapy, it will be essential to dissect out its cytoprotective pathways. Our goal for
this proposal is to determine the mechanisms through which MIF antagonizes the development of emphysema.
Our preliminary data suggests MIF mediates its protective effects through its receptor CD74. Our hypothesis is
MIF protects against the development of emphysema by mitigating CS-mediated endothelial senescence in a
CD74 dependent manner. In Aim 1, we will define the mechanism through which the MIF-CD74 interaction
reduces endothelial senescence. In Aim 2, we will determine the role of endothelial CD74 in regulating
susceptibility to emphysema. In Aim 3, we will determine the therapeutic potential of targeting MIF-CD74
interactions in emphysema. Completion of these aims will significantly advance our understanding of the
pathogenesis of emphysema and may identify precision-based approaches based on MIF biology for treating
patients with emphysema.

Grant Number: 5R01HL155948-05
NIH Institute/Center: NIH
Principal Investigator: RICHARD BUCALA