Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts
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 lun...
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doaj-afb0567058dd4a4db74a1069f67096062020-11-25T02:38:23ZengMDPI AGCells2073-44092020-02-019241110.3390/cells9020411cells9020411Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung MyofibroblastsDavid Nareznoi0Jenya Konikov-Rozenman1Dmytro Petukhov2Raphael Breuer3Shulamit B. Wallach-Dayan4Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah Medical Research Center, PO Box 12000, Kiryat Hadassah, Jerusalem 91120, IsraelLung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah Medical Research Center, PO Box 12000, Kiryat Hadassah, Jerusalem 91120, IsraelLung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah Medical Research Center, PO Box 12000, Kiryat Hadassah, Jerusalem 91120, IsraelLung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah Medical Research Center, PO Box 12000, Kiryat Hadassah, Jerusalem 91120, IsraelLung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah Medical Research Center, PO Box 12000, Kiryat Hadassah, Jerusalem 91120, IsraelA 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<sup>+</sup> 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.https://www.mdpi.com/2073-4409/9/2/411pulmonary fibrosislung myofibroblastsmatrix metalloproteinase (mmp)soluble fasl (sfasl)cell death |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
David Nareznoi Jenya Konikov-Rozenman Dmytro Petukhov Raphael Breuer Shulamit B. Wallach-Dayan |
spellingShingle |
David Nareznoi Jenya Konikov-Rozenman Dmytro Petukhov Raphael Breuer Shulamit B. Wallach-Dayan Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts Cells pulmonary fibrosis lung myofibroblasts matrix metalloproteinase (mmp) soluble fasl (sfasl) cell death |
author_facet |
David Nareznoi Jenya Konikov-Rozenman Dmytro Petukhov Raphael Breuer Shulamit B. Wallach-Dayan |
author_sort |
David Nareznoi |
title |
Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts |
title_short |
Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts |
title_full |
Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts |
title_fullStr |
Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts |
title_full_unstemmed |
Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts |
title_sort |
matrix metalloproteinases retain soluble fasl-mediated resistance to cell death in fibrotic-lung myofibroblasts |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2020-02-01 |
description |
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<sup>+</sup> 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. |
topic |
pulmonary fibrosis lung myofibroblasts matrix metalloproteinase (mmp) soluble fasl (sfasl) cell death |
url |
https://www.mdpi.com/2073-4409/9/2/411 |
work_keys_str_mv |
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