MIF‐CD74 Signaling Protects against Endothelial Senescence in Chronic Obstructive Pulmonary Disease

RATIONALE Chronic obstructive pulmonary disease (COPD) is characterized by gradual destruction of alveolar architecture and subsequent airflow obstruction. Advancing age and significant exposure to cigarette smoke (CS) are common risk factors, yet the pathologic manifestations of COPD are heterogenous and the biologic risk factors for COPD are unclear. MIF is an important regulator of innate immunity, cellular homeostasis and survival. We previously reported that circulating MIF was lower in smokers with COPD compared with smokers without COPD. Others have confirmed these findings and correlated decreased MIF protein with greater radiologic/functional evidence of emphysema in patients. METHODS Gene expression microarray analysis was performed on lung tissue from individuals with/without COPD (n=262), and endothelial cell (Ec) CD74 expression was analyzed in single‐cell RNA‐seq (control=19, COPD=29). CD74 expression was determined by immunohistochemistry in human lung. CS extract (CSE) treated to HUVEC along with the following recombinant‐MIF (rMIF), MIF‐siRNA, neutralizing anti‐MIF monoclonal antibody (anti‐MIF mAb), MIF098 (MIF antagonist), or MIF20 (MIF agonist). U0126 (ERK inhibitor) was treated 1 hour prior to MIF20 treatment. MIF‐KO mice were treated with a control or MIF expressing lentiviral‐vector. Ec were isolated via MACS sorting. AKR/J mice were exposed to CS (4 months), and MIF20 was administered orally (3 mg/mouse) to mice every day for the final 2 months of CS exposure. Pressure‐Volume (PV) loops were measured by FlexiVent. RESULTS CD74 expression was increased in COPD patients especially in lung Ec. CSE increased p16 and p21 mRNA expression in HUVEC. This increase was attenuated by rMIF or MIF20, while augmented by anti‐MIF mAb or MIF98. CSE increased SA‐β‐gal activity and MIF20 attenuated it. The protective effect of MIF20 against CS‐induced Ec senescence was abolished by ERK signaling inhibitor. MIF‐KO mice showed an upshift of PV loop and increased Ec p21 expression, which were attenuated by restoration of MIF expression. CS induced upshift of PV loop, increased p16 and p21 expression, which were attenuated by MIF20. CONCLUSIONS The expression of CD74, the cognate receptor for MIF, was increased in COPD. Senescence was induced in Ec by CS, an important causative factor for COPD. MIF20, a novel small molecule MIF agonist, attenuated CS‐induced senescence via ERK signaling, which is known to support cell survival and proliferation. Furthermore, MIF20 prevented CS‐induced lung emphysema. These data suggest that therapeutic modulation of MIF targeting in lung Ec is feasible represents a novel strategy to protect against senescence‐induced COPD. Support or Funding Information M.S. is supported by NIH/NHLBI K08HL135402 and FAMRI YCSA 142017. P.J.L. is supported by NIH/NHLBI R01 HL138386, VAORD11858595, US Department of Defense PR150809, and FAMRI 150074.