Idiopathic pulmonary fibrosis fibroblasts become resistant to Fas ligand‐dependent apoptosis via the alteration of decoy receptor 3

Abstract

Idiopathic pulmonary fibrosis (IPF) is an irreversible lethal lung disease with an unknown aetiology. IPF patient’s lung fibroblasts express inappropriately high Akt activity, protecting them in response to an apoptosis-inducing type I collagen matrix. FasL, a ligand for Fas, is known to be increased in the lung tissues of patients with IPF, implicated with the progression of IPF. Expression of Decoy Receptor3 (DcR3) which binds to FasL, thereby subsequently suppressing the FasL/Fas-dependent apoptotic pathway is frequently altered in various human disease. However, the role of DcR3 in IPF fibroblasts in regulating their viability has not been examined. We found that enhanced DcR3 expression exists in the majority of IPF fibroblasts on collagen matrices, resulting in the protection of IPF fibroblasts from FasL-induced apoptosis. Abnormally high Akt activity suppresses GSK-3β function, thereby accumulating the nuclear factor of activated T-cells c1 (NFATc1) in the nucleus, increasing DcR3 expression in IPF fibroblasts. This alteration protects IPF cells from FasL-induced apoptosis on collagen. However, the inhibition of Akt or NFATc1 decreases DcR3 mRNA and protein levels, which sensitizes IPF fibroblasts to FasL-mediated apoptosis. Furthermore, enhanced DcR3 and NFATc1 expression is mainly present in myofibroblasts in the fibroblastic foci of lung tissues derived from IPF patients. Our results showed that when IPF cells interacted with collagen matrix, aberrantly activated Akt increased DcR3 expression via GSK-3β/NFATc1 and protected IPF cells from the FasL-dependent apoptotic pathway. These findings suggest that the inhibition of DcR3 function may be an effective approach for sensitizing IPF fibroblasts in response to FasL, limiting the progression of lung fibrosis.

FoxM1-dependent RAD51 and BRCA2 signaling protects idiopathic pulmonary fibrosis fibroblasts from radiation-induced cell death

“…Our prior studies demonstrated that abnormally low FoxO3a protects IPF fibroblasts from collagen-rich matrix-driven apoptosis 9 , 10 , 32 . In this study, we elucidated that FoxO3a alteration directly contributes to reduced DNA damage via the FoxM1/RAD51–BRCA2-dependent axis, fortifying the crucial role of FoxO3a in IPF fibroblasts.…”

“…Our data also support that radiation preferentially damages normal lung epithelial cells and fibroblasts, whereas resident pathological pro-fibrotic fibroblasts, which may be inhabitant in small numbers, are likely to survive and contribute to the fibrotic process. Fibrosis-inducing cells such as IPF fibroblasts flourish in collagen-rich conditions 9 , 10 , 32 , therefore the normal healing process following radiation injury may provide an environment that favors fibrosis. It is feasible that the presence of even a small population of pro-fibrotic lung fibroblasts in cancer patients may be at an increased risk of RILF following treatment.…”

Regulation of fibroblast Fas expression by soluble and mechanical pro-fibrotic stimuli

“…In recent years, a number of mechanisms involving inhibitor of apoptosis family proteins, BCL-2 family proteins, pro-survival protein kinase activation and cell-matrix interactions have been shown to regulate fibroblast susceptibility to apoptosis and accumulating studies demonstrate the feasibility of targeting fibroblast survival as a treatment strategy for fibrotic disease in the lung [ 1 , 4 , 21 , 24 , 36 , 37 ]. Additionally, several studies now indicate that regulation of Fas itself may contribute to fibroblast acquisition of an apoptosis-resistant phenotype, although our understanding of the underlying mechanisms continues to evolve [ 7 , 16 , 20 , 38 ]. In the current study, we have shown that pro-fibrotic soluble and mechanical stimuli suppress fibroblast expression of Fas through both transcriptional and post-transcriptional mechanisms, that decreased Fas correlates with resistance to apoptosis, and that enhanced apoptosis susceptibility in response to inflammatory cytokines is not diminished by TGF-β1 treatment.…”

Probing into the Mechanism of Alkaline Citrus Extract Promoted Apoptosis in Pulmonary Fibroblasts of Bleomycin‐Induced Pulmonary Fibrosis Mice

“…The first is the death receptor-regulated membrane receptor apoptosis pathway. In this pathway, Caspase 8 is activated by Fas and its ligand FasL, and then it activates the membrane receptor apoptosis pathway [ 24 ]. The second is mitochondria apoptosis pathway.…”