Role of IRE1α/XBP-1 in Cystic Fibrosis Airway Inflammation

Abstract

Cystic fibrosis (CF) pulmonary disease is characterized by chronic airway infection and inflammation. The infectious and inflamed CF airway environment impacts on the innate defense of airway epithelia and airway macrophages. The CF airway milieu induces an adaptation in these cells characterized by increased basal inflammation and a robust inflammatory response to inflammatory mediators. Recent studies have indicated that these responses depend on activation of the unfolded protein response (UPR). This review discusses the contribution of airway epithelia and airway macrophages to CF airway inflammatory responses and specifically highlights the functional importance of the UPR pathway mediated by IRE1/XBP-1 in these processes. These findings suggest that targeting the IRE1/XBP-1 UPR pathway may be a therapeutic strategy for CF airway disease.

Mucosal humoral immunity in cystic fibrosis - a tangled web of failed proteostasis, infection and adaptive immunity

“…For example, raised levels of IL-17 were not found in the CF patients in contrast to prior studies including young children [7][8][9]. The role of the UPR in CF remains unclear, with some studies implicating a direct effect of F508del misfolding while others find key UPR inducers come indirectly from the inflammatory milieu that may be variably induced by the many pathogens capable of transiently or chronically infecting the CF airway [5], or even by sterile inflammation prior to infection. The role of impaired autophagy implicated in CF on sIgA remains unexplored.…”

ACE-2/ANG1-7 ameliorates ER stress-induced apoptosis in seawater aspiration-induced acute lung injury

“…Based on the effect of ACE-2/ANG1-7, we tried to design a targeted treatment method that makes ACE-2/ANG1-7 work only in damaged or preapoptotic cells. In the process of ER stress, phosphorylation of IRE1 can splice XBP1u mRNA to XBP1s mRNA, which can encode XBP1s protein in a short period of time (21). XBP1s has almost no expression in normal lung tissues and seawater stimulation activated the expression of p-IRE1/XBP1s in damaged cells.…”

The isoprenoid end product N6-isopentenyladenosine reduces inflammatory response through the inhibition of the NFκB and STAT3 pathways in cystic fibrosis cells

“…To investigate this issue, we analyzed the effect of iPA on IL-8 and RANTES release in CuFi-1 (CFTR ΔF508/ΔF508 ) and NuLi-1 cell lines (CFTR wild type) which are both telomerase-immortalized airway cells, characterized by the ability to constitute a polarized monolayer with a transepithelial activity that mimics the behavior of CF airway epithelial cells in vivo [ 20 ]. CuFi-1 cells show overexpression of a number of signal transduction pathways including MAPK/ERK and NFκB that are responsible for the overactivation of several inflammatory and oxidative stress genes such as IL-6, IL-8 and RANTES [ 33 , 34 ]. The use of these two cell systems allowed us to ascertain whether the effect of iPA was related to the CFTR mutation or was a common anti-inflammatory effect.…”

“…Our findings are in agreement with Dassano et al [ 32 ] who showed that in breast cancer and HL-60 cells induced to differentiate in neutrophilic lineage, iPA was able to trigger the NRF-mediated oxidative response through the induction of gene encoding detoxifying and anti-oxidant enzymes—such as heme oxygenase-1 gene and glutamate-cysteine ligase (GCLC)—that protect cells against ROS and reactive metabolites. In conclusion, as airway epithelial cells contribute significantly to airway inflammation in patients with CF [ 34 , 36 ]. The fine tuning of cyto-chemokines secretion by iPA along with its ability to improve selenoprotein expression might be an attractive therapeutic approach to reduce excessive airway inflammation which is a major cause of CF morbidity.…”