Hung Nguyen, PhD
Rank
Instructor
Department
Medicine
Pulmonary and Critical Care Medicine; and Rheumatology
Authors
Hung N. Nguyen*, Yunju Jeong, Yunhye Kim, Hyunbum Kim, Merriam T. Louis, Yaunghyun H Kim, Aidan Cullen, Humra Athar, Patrick Gavin, Muhammad D. Sheikh, Reshmi Manandhar, Ke Yuan, Michael B. Brenner, Edy Y. Kim
Principal Investigator
Edy Y. Kim
Twitter / Website
Categories
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease (ILD) with a high mortality rate. Current treatment options are limited in efficacy and have broad mechanisms. Highly targeted therapies for IPF have failed in part due to the diversity of pro-fibrotic stimuli upstream of fibroblasts. Here, we demonstrate that leukemia inhibitory factor (LIF), via its receptor (LIFR), is a “master amplifier” of multiple upstream pro-fibrotic activators, including IL-4, IL-13 and TGFb. We observed higher expression of LIF in bulk tissue RNAseq of human IPF lung explant vs. control as well as in single cell RNAseq of IPF vs. healthy fibroblasts from lung tissues. Also, following TGFb stimulation of human lung fibroblasts derived from ILD donors, LIF was strongly upregulated along with key fibrotic gene markers including COL1A1, COL1A2, POSTN and ACTA2. Using LIFR siRNA or blocking antibody, we found that blockade of LIF-LIFR signaling reduced the induction of pro-fibrotic program by TGFb. Moreover, blockade of LIFR signaling also reduced the pro-fibrotic effects of IL-4 or IL-13. This suggested that LIF acts via LIFR as an autocrine amplification loop in fibroblasts downstream of multiple pro-fibrotic stimuli. Notably, this loop operates independently of IL-11. Using small molecular inhibitors or siRNA against JAK kinases, JAK2 was found to act downstream of LIFR. To demonstrate that targeting LIFR was beneficial for treating fibrosis, we blocked LIFR in human IPF precision cut lung slice (PCLS) and observed significant reduction in fibrotic gene expression. As a master amplifier that integrates several upstream profibrotic or proinflammatory stimuli, LIF/LIFR may serve as a single target to address an unmet therapeutic need for treatment of a wide range of fibrotic and inflammatory disorders, including IPF or autoimmune diseases.