Cutting edge: FasL+ immune cells promote resolution of fibrosis

Wallach-Dayan, Shulamit B.; Elkayam, Liron; Golan-Gerstl, Regina; Konikov, Jenya; Zisman, Philip; Dayan, Mark Richter; Breuer, Raphael

doi:10.1016/j.jaut.2015.02.006

Cited by 28 publications

(39 citation statements)

References 55 publications

(65 reference statements)

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“…Past studies have shown increased levels of soluble FasL in BAL fluids from patients with IPF, and FasL increased apoptosis of epithelial cells in vitro [12, 21–23]. Recently, a potential anti-fibrotic effect of FasL-positive immune cells has been proposed [24]. PICP is known to be an early marker of collagen synthesis in cardiac and hepatic fibrosis [25, 26].…”

Section: Introductionmentioning

confidence: 99%

MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis

Bauer

White

Bernard³

et al. 2017

ERJ Open Res

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Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis, which is characterised by destruction of normal lung architecture and excessive deposition of lung extracellular matrix. The heterogeneity of disease progression in patients with IPF poses significant obstacles to patient care and prevents efficient development of novel therapeutic interventions. Blood biomarkers, reflecting pathobiological processes in the lung, could provide objective evidence of the underlying disease.Longitudinally collected serum samples from the Bosentan Use in Interstitial Lung Disease (BUILD)-3 trial were used to measure four biomarkers (metalloproteinase-7 (MMP-7), Fas death receptor ligand, osteopontin and procollagen type I C-peptide), to assess their potential prognostic capabilities and to follow changes during disease progression in patients with IPF.In baseline BUILD-3 samples, only MMP-7 showed clearly elevated protein levels compared with samples from healthy controls, and further investigations demonstrated that MMP-7 levels also increased over time. Baseline levels of MMP-7 were able to predict patients who had higher risk of worsening and, notably, baseline levels of MMP-7 could predict changes in FVC as early as month 4.MMP-7 shows potential to be a reliable predictor of lung function decline and disease progression.

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Section: Introductionmentioning

confidence: 99%

MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis

Bauer

White

Bernard³

et al. 2017

ERJ Open Res

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“…It has been previously reported by us [42] and others [45] that normal lung myofibroblasts, but not those from fibrotic lungs in bleomycin-treated mice and in humans with IPF, are susceptible to apoptosis induced by Fas agonists and immune T cells. mFasL can also induce cell death [18,45], and sFasL (sFasL) contributes to the resistance to Fas-and immune cell-induced death [32]. Having shown [42], that IPF-media can induce resistance to cell death in normal lung myofibroblasts as in IPF-cells due to the elevated levels of sFasL in the medium, we blocked the cleavage of FasL that was initiated by MMP using MMP inhibitor batimastat (10 µM, for 24 h), compared to the vehicle (DMSO).…”

Section: Resultsmentioning

confidence: 99%

“…MMP-7 is known to be produced by both alveolar epithelial cells and myofibroblasts, and it plays a role in various processes associated with the initiation and progression of pulmonary fibrosis, such as epithelial-mesenchymal transition, extracellular matrix degradation, aberrant matrix repair, and tissue remodeling [26,28,30,31]. As sFasL demonstrates the capacity to promote fibroblast survival and apoptotic resistance [32], and MMP-7 is an important FasL shedder [33], the involvement of MMP-7 in cell survival may be conjectured. There are indications that MMP-7 may play a part in promoting cell survival and resistance to apoptosis [34], for example via the cleavage of osteopontin [35], which in turn may be upregulated via RUNX2 expression [36].…”

Section: Introductionmentioning

confidence: 99%

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

Nareznoi

Konikov-Rozenman

Petukhov

et al. 2020

Cells

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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.

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“…Further studies will therefore be required to identify the importance of H 2 O 2 and the source of its production for GSTP-linked S-glutathionylation in settings of fibrosis. While FAS signaling is important for epithelial cell apoptosis, it has also been linked to myofibroblast activation, proliferation, and evasion from apoptosis (6, 9, 42–44). Our current study did not determine whether GSTP and S-glutathionylation chemistry plays a role in myofibroblast behavior, which will require additional investigation.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π

McMillan¹,

Velden²,

Lahue³

et al. 2016

JCI Insight

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Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by excessive collagen production and fibrogenesis. Apoptosis in lung epithelial cells is critical in IPF pathogenesis, as heightened loss of these cells promotes fibroblast activation and remodeling. Changes in glutathione redox status have been reported in IPF patients. S-glutathionylation, the conjugation of glutathione to reactive cysteines, is catalyzed in part by glutathione-S-transferase π (GSTP). To date, no published information exists linking GSTP and IPF to our knowledge. We hypothesized that GSTP mediates lung fibrogenesis in part through FAS S-glutathionylation, a critical event in epithelial cell apoptosis. Our results demonstrate that GSTP immunoreactivity is increased in the lungs of IPF patients, notably within type II epithelial cells. The FAS-GSTP interaction was also increased in IPF lungs. Bleomycin- and AdTGFβ-induced increases in collagen content, α-SMA, FAS S-glutathionylation, and total protein S-glutathionylation were strongly attenuated in Gstp−/− mice. Oropharyngeal administration of the GSTP inhibitor, TLK117, at a time when fibrosis was already apparent, attenuated bleomycin- and AdTGFβ-induced remodeling, α-SMA, caspase activation, FAS S-glutathionylation, and total protein S-glutathionylation. GSTP is an important driver of protein S-glutathionylation and lung fibrosis, and GSTP inhibition via the airways may be a novel therapeutic strategy for the treatment of IPF.

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Cutting edge: FasL+ immune cells promote resolution of fibrosis

Cited by 28 publications

References 55 publications

MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis

MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis

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

Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π

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