Targeting MAP3K19 prevents human lung myofibroblast activation both in vitro and in a humanized SCID model of idiopathic pulmonary fibrosis

Isabelle C Jones,Tai Wei Ly,Cory M Hogaboam,Rohan Narayanan,Stefen A Boehme,Kevin B Bacon,Ana L Coelho,Milena S Espindola,David M Habiel

doi:10.1038/s41598-019-56393-z

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a disease with a devastating prognosis characterized by unrelenting lung scarring. Aberrant activation of lung fibroblasts is a key feature of this disease, yet the key pathways responsible for this are poorly understood. Mitogen-activated protein kinase, kinase, kinase- 19 (MAP3K19) was recently shown to be upregulated in IPF and this MAPK has a key role in target gene transcription in the TGF-β pathway. Herein, we further investigate the role of MAP3K19 in cultured normal and IPF fibroblasts and in a humanized SCID mouse model of IPF employing both short interfering (si) RNA and novel small-molecule inhibitors directed at this kinase. Targeting MAP3K19 had significant inhibitory effects on the expression of both alpha smooth muscle actin and extracellular matrix in cultured human IPF fibroblasts. Quantitative protein and biochemical assays, as well as histological analysis, showed that MAP3K19 was required for the development of lung fibrosis in SCID mice humanized with IPF lung fibroblasts. MAP3K19 was required for IPF myofibroblast differentiation, and targeting its activity attenuated the profibrotic activity of these cells both in vitro and in an adoptive transfer SCID model of pulmonary fibrosis.

Highlights

Idiopathic Pulmonary Fibrosis (IPF) is a disease with a devastating prognosis characterized by unrelenting lung scarring
IPF fibroblasts from patients who exhibited slow progression or stable disease expressed the highest transcript expression of MAP3K19 compared with normal fibroblasts or IPF fibroblasts derived from IPF patients who exhibited rapid progression of disease (Fig. 1B)
Previous studies had indicated that targeting MAP3K19 in the context of experimental smoke-induced[7] and bleomycin-induced[8] lung injury and remodeling was therapeutic in both models via mechanisms involving inflammation and TGF-β-induced remodeling

Summary

Introduction

Idiopathic Pulmonary Fibrosis (IPF) is a disease with a devastating prognosis characterized by unrelenting lung scarring. We further investigate the role of MAP3K19 in cultured normal and IPF fibroblasts and in a humanized SCID mouse model of IPF employing both short interfering (si) RNA and novel small-molecule inhibitors directed at this kinase. MAP3K19 was required for IPF myofibroblast differentiation, and targeting its activity attenuated the profibrotic activity of these cells both in vitro and in an adoptive transfer SCID model of pulmonary fibrosis. We report the effects of both siRNA and novel small-molecule inhibitors of MAP3K19 in primary human IPF fibroblasts and a SCID mouse model of IPF induced by the intravenous injection of IPF fibroblasts[9,10]

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