Abstract
Cigarette smoking is a major risk factor for the inflammatory disease, chronic obstructive pulmonary disease (COPD). The mechanism by which cigarette smoke (CS) induces chronic lung inflammation is still largely unknown. We hypothesize that immunogenic airway epithelial cell death is involved in the initiation of the inflammatory response. We previously identified CFLAR, the gene encoding the cell death regulator protein c-FLIP, to be associated with CS-induced release of damage-associated molecular patterns (DAMPs). Here, we investigated the effect of CS on expression levels of CFLAR in bronchial biopsies from smokers and non-smokers and CFLAR transcript isoform-expression in a dataset of air-liquid interface-differentiated bronchial epithelial cells. Furthermore, CFLAR was down-regulated by siRNA in lung epithelial A549 cells, followed by investigation of the effects on apoptosis, necrosis and DAMP release. CS exposure significantly decreased CFLAR expression in bronchial epithelial cells. Moreover, we observed a shift in relative abundance of the isoforms c-FLIPS and c-FLIPL transcripts in bronchial biopsies of current smokers compared to non-smokers, consistent with a shift towards necroptosis. In vitro, down-regulation of CFLAR increased apoptosis at baseline as well as CS extract-induced necrosis and DAMP release. In conclusion, CS exposure decreases CFLAR expression, which might increase susceptibility to immunogenic cell death.
Highlights
Cigarette smoking is a major cause of morbidity and mortality worldwide, leading to various diseases including cardio-vascular diseases, lung cancer and chronic obstructive pulmonary disease (COPD)[1]
We found a trend for an increase of the c-FLIPS:c-FLIPL ratio reflecting what was observed in the bronchial biopsies (Fig. 2C)
We showed for the first time that the expression of CFLAR in the airways is decreased upon cigarette smoke (CS) exposure both in vitro and in vivo
Summary
Cigarette smoking is a major cause of morbidity and mortality worldwide, leading to various diseases including cardio-vascular diseases, lung cancer and chronic obstructive pulmonary disease (COPD)[1]. A region associated with the gene CFLAR9, which encodes the apoptosis and necroptosis regulator protein c-FLIP. The 14 exon CFLAR gene produces 13 splice variants of which three are expressed as proteins[10], one 55 kDa long isoform (c-FLIPL) and two short isoforms, c-FLIPS, and c-FLIPR (26 kDa and 24 kDa respectively). CFLAR has been identified as a susceptibility gene for CS-induced neutrophilic airway inflammation[9], but no studies have been performed investigating the role of CFLAR in COPD and CS-induced pulmonary inflammation. We hypothesize that CFLAR expression is decreased upon smoking which increases the susceptibility for CS-induced epithelial immunogenic cell death with subsequent DAMP release, which may induce pulmonary inflammation in COPD patients. We studied the functional effect of CFLAR down-regulation on CS-induced cell death and DAMP release in an alveolar epithelial cell line in vitro. We investigated bronchial CFLAR expression and CFLAR splice variant abundance in bronchial biopsies from current smokers and non-smokers
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