Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts.

David Nareznoi,Shulamit B Wallach-Dayan,Raphael Breuer,Dmytro Petukhov,Jenya Konikov-Rozenman

doi:10.3390/cells9020411

David Nareznoi, Shulamit B Wallach-Dayan + Show 3 more

Open Access

https://doi.org/10.3390/cells9020411

Copy DOI

Journal: Cells	Publication Date: Feb 11, 2020
Citations: 9	License type: CC BY 4.0

Affiliation: Hadassah Medical Center, Boston University

Abstract

A prominent feature of obstructed tissue regeneration following injury in general, and fibrotic lung tissue in particular, is fibroblast proliferation and accumulation. The Fas/FasL apoptotic pathway has been shown to be involved in human idiopathic pulmonary fibrosis (IPF) and bleomycin-induced lung fibrosis in rodents. We previously showed that in normal injury repair, myofibroblasts’ accumulation is followed by their decline by FasL+ T cell-induced cell death. In pathological lung fibrosis, myofibroblasts resist cell death and accumulate. Like other members of the tumor necrosis factor (TNF) family, membrane-bound FasL can be cleaved from the cell surface to generate a soluble form (sFasL). Metalloproteinases (MMPs) are known to convert the membrane-bound form of FasL to sFasL. MMP-7 knockout (KO) mice were shown to be protected from bleomycin (BLM)-induced lung fibrosis. In this study, we detected increased levels of sFasL in their blood serum, as in the lungs of patients with IPF, and IPF-lung myofibroblast culture medium. In this study, using an MMP-inhibitor, we showed that sFasL is decreased in cultures of IPF-lung myofibroblasts and BLM-treated lung myofibroblasts, and in the blood serum of MMP-7KO mice. Moreover, resistant fibrotic-lung myofibroblasts, from the lungs of humans with IPF and of BLM-treated mice, became susceptible to T-cell induced cell death in a co-culture following MMP-inhibition- vs. control-treatment or BLM-treated MMP-7KO vs. wild-type mice, respectively. sFasL may be an unrecognized mechanism for MMP-7-mediated decreased tissue regeneration following injury and the evolution of lung fibrosis.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease characterized by the lack of tissue regeneration and formation of scar tissue within the lungs, in the absence of any known provocation [1,2]
We aimed to assess our hypothesis that matrix metalloproteinase (MMP) are responsible for the increased surface to generate a soluble form (sFasL) levels that we had previously detected in the culture medium of IPF-lung myofibroblasts [38]
The membrane-bound Fas ligand (FasL) (mFasL) levels were assessed in cultured cell-lysates and were found to be higher following the MMP inhibitor treatment of normal-lung myofibroblasts, from an OD of 0.5 ± 0.1SD to 0.9 ± 0.2SD, but with comparable levels in the IPF cells, which were relatively higher in the baseline levels 0.9–1 OD (Figure 1B; mFasL in IPF or NL cells +Ctrl or +MMP inhibitor)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease characterized by the lack of tissue regeneration and formation of scar tissue within the lungs, in the absence of any known provocation [1,2]. The median survival of patients with IPF is approximately 3 years from the time of diagnosis [3]. It is characterized by alveolar epithelial injury, inflammatory cell accumulation, myofibroblast hyperplasia, the deposition of extracellular matrix and scars. T lymphocytes have been found in close proximity to interstitial myofibroblasts during pulmonary fibrosis [10], and a direct relationship between the presence of T cells and myofibroblast apoptosis has been reported [11]. T cell-myofibroblast interaction has been shown to play a role in a number of physiological as well as pathological states, including the regulation of wound healing [12,13]

Objectives

Methods

Results

Conclusion