Abstract:The continuous infection-inflammation cycle plays a crucial role in the progression of cystic fibrosis (CF) disease. This noxious loop can be aggravated by a reduced partial pressure of oxygen in the blood, hypoxemia, present in CF patients. These interconnected factors, hypoxia, inflammation and infection, by stabilizing the hypoxia-inducible factor-1α (HIF-1α) protein subunit, are able to activate the transcription factor HIF-1. To date, data investigating the potential role of HIF-1 in CF are scarce. Our re… Show more
“…For this, IB3-1 airway epithelial cells were infected with P. aeruginosa strain PAO1 in the absence or the presence of CDCA. Infection by PAO1 for 3 h at an MOI of 25:1 led to HIF-1␣ protein stabilization in IB3-1 airway epithelial cells, as previously published (31) (Fig. 6B).…”
Section: Resultssupporting
confidence: 87%
“…Since then, several other signals have been described. More recently, infections with human pathogens (25)(26)(27)(28)(29)(30), including P. aeruginosa (30)(31)(32), and chronic inflammation, e.g., rheumatoid arthritis (21), have been shown to stabilize HIF-1␣ in immune and/or epithelial cells. Consequently, HIF-1 induces genes involved in the host immune response, such as antimicrobial peptides, nitric oxide, and several cytokines, including TNF-␣, which help in the fight against and limit the spread of infection (30).…”
bGastroesophageal reflux (GER) frequently occurs in patients with respiratory disease and is particularly prevalent in patients with cystic fibrosis. GER is a condition in which the duodenogastric contents of the stomach leak into the esophagus, in many cases resulting in aspiration into the respiratory tract. As such, the presence of GER-derived bile acids (BAs) has been confirmed in the bronchoalveolar lavage fluid and sputum of affected patients. We have recently shown that bile causes cystic fibrosis-associated bacterial pathogens to adopt a chronic lifestyle and may constitute a major host trigger underlying respiratory infection. The current study shows that BAs elicit a specific response in humans in which they repress hypoxia-inducible factor 1␣ (HIF-1␣) protein, an emerging master regulator in response to infection and inflammation. HIF-1␣ repression was shown to occur through the 26S proteasome machinery via the prolyl hydroxylase domain (PHD) pathway. Further analysis of the downstream inflammatory response showed that HIF-1␣ repression by BAs can significantly modulate the immune response of airway epithelial cells, correlating with a decrease in interleukin-8 (IL-8) production, while IL-6 production was strongly increased. Importantly, the effects of BAs on cytokine production can also be more dominant than the bacterium-mediated effects. However, the effect of BAs on cytokine levels cannot be fully explained by their ability to repress HIF-1␣, which is not surprising, given the complexity of the immune regulatory network. The suppression of HIF-1 signaling by bile acids may have a significant influence on the progression and outcome of respiratory disease, and the molecular mechanism underpinning this response warrants further investigation.
“…For this, IB3-1 airway epithelial cells were infected with P. aeruginosa strain PAO1 in the absence or the presence of CDCA. Infection by PAO1 for 3 h at an MOI of 25:1 led to HIF-1␣ protein stabilization in IB3-1 airway epithelial cells, as previously published (31) (Fig. 6B).…”
Section: Resultssupporting
confidence: 87%
“…Since then, several other signals have been described. More recently, infections with human pathogens (25)(26)(27)(28)(29)(30), including P. aeruginosa (30)(31)(32), and chronic inflammation, e.g., rheumatoid arthritis (21), have been shown to stabilize HIF-1␣ in immune and/or epithelial cells. Consequently, HIF-1 induces genes involved in the host immune response, such as antimicrobial peptides, nitric oxide, and several cytokines, including TNF-␣, which help in the fight against and limit the spread of infection (30).…”
bGastroesophageal reflux (GER) frequently occurs in patients with respiratory disease and is particularly prevalent in patients with cystic fibrosis. GER is a condition in which the duodenogastric contents of the stomach leak into the esophagus, in many cases resulting in aspiration into the respiratory tract. As such, the presence of GER-derived bile acids (BAs) has been confirmed in the bronchoalveolar lavage fluid and sputum of affected patients. We have recently shown that bile causes cystic fibrosis-associated bacterial pathogens to adopt a chronic lifestyle and may constitute a major host trigger underlying respiratory infection. The current study shows that BAs elicit a specific response in humans in which they repress hypoxia-inducible factor 1␣ (HIF-1␣) protein, an emerging master regulator in response to infection and inflammation. HIF-1␣ repression was shown to occur through the 26S proteasome machinery via the prolyl hydroxylase domain (PHD) pathway. Further analysis of the downstream inflammatory response showed that HIF-1␣ repression by BAs can significantly modulate the immune response of airway epithelial cells, correlating with a decrease in interleukin-8 (IL-8) production, while IL-6 production was strongly increased. Importantly, the effects of BAs on cytokine production can also be more dominant than the bacterium-mediated effects. However, the effect of BAs on cytokine levels cannot be fully explained by their ability to repress HIF-1␣, which is not surprising, given the complexity of the immune regulatory network. The suppression of HIF-1 signaling by bile acids may have a significant influence on the progression and outcome of respiratory disease, and the molecular mechanism underpinning this response warrants further investigation.
“…A549 (ATCC CCL-185) is a lung adenocarcinoma epithelial cell line derived for a patient with a lung carcinoma. IB3-1 and S9 cells were cultured using LHC-8 medium (Invitrogen) as previously described (26). CFTE and A549 cells were cultured using minimal essential medium (MEM) M7278 supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 units/ml penicillin, and 100 g/ml streptomycin.…”
Section: Cfte29omentioning
confidence: 99%
“…To date, a number of Enterobacteriaceae species (18), including Escherichia coli (3), Chlamydia (44,49), Pseudomonas aeruginosa (26,40,48), and group A Streptococcus (39,40), have all been shown to stabilize HIF-1␣ in both immune and epithelial cells. Stabilization of HIF-1␣ and subsequent HIF-1 activation promote the release of antimicrobial peptides such as cathelicidins and granule proteases and stimulate the production of nitric oxide and tumor necrosis factor alpha (TNF-␣) (34,40).…”
mentioning
confidence: 99%
“…As to date, bacteria and bacterial compounds have been shown to lead to HIF-1␣ protein accumulation (3,15,18,25,26,39,40,44,49,55), it was therefore unexpected to find that P. aeruginosa AQ signaling molecules suppressed HIF-1␣ protein levels. Destabilization occurred through degradation by the 26S proteasome machinery and resulted in modulation of the HIF-1 target gene HKII.…”
bThe transcription factor hypoxia-inducible factor 1 (HIF-1) has recently emerged to be a crucial regulator of the immune response following pathogen perception, including the response to the important human pathogen Pseudomonas aeruginosa. However, as mechanisms involved in HIF-1 activation by bacterial pathogens are not fully characterized, understanding how bacteria and bacterial compounds impact on HIF-1␣ stabilization remains a major challenge. In this context, we have focused on the effect of secreted factors of P. aeruginosa on HIF-1 regulation. Surprisingly, we found that P. aeruginosa cell-free supernatant significantly repressed HIF-1␣ protein levels. Further characterization revealed that HIF-1␣ downregulation was dependent on a subset of key secreted factors involved in P. aeruginosa pathogenesis, the 2-alkyl-4-quinolone (AQ) quorum sensing (QS) signaling molecules, and in particular the pseudomonas quinolone signal (PQS). Under hypoxic conditions, the AQ-dependent downregulation of HIF-1␣ was linked to the suppressed induction of the important HIF-1 target gene hexokinase II. Furthermore, we demonstrated that AQ molecules directly target HIF-1␣ protein degradation through the 26S-proteasome proteolytic pathway but independently of the prolyl hydroxylase domain (PHD). In conclusion, this is the first report showing that bacterial molecules can repress HIF-1␣ protein levels. Manipulation of HIF-1 signaling by P. aeruginosa AQs could have major consequences for the host response to infection and may facilitate the infective properties of this pathogen.
Adaptation to hypoxia is an essential physiological response to decrease in tissue oxygenation. This process is primarily under the control of transcriptional activator hypoxia-inducible factor (HIF1). A better understanding of the intracellular HIF1 stabilization pathway would help in management of various diseases characterized by anemia. Among human pathologies, cystic fibrosis disease is characterized by a chronic anemia that is inadequately compensated by the classical erythroid response mediated by the HIF pathway. Because the kidney expresses CFTR and is a master organ involved in the adaptation to hypoxia, we used renal cells to explore the relationship between CFTR and the HIF1-mediated pathway. To monitor the adaptive response to hypoxia, we engineered a hypoxia-induced fluorescent reporter system to determine whether CFTR modulates hypoxia-induced HIF1 stabilization. We show that CFTR is a regulator of HIF stabilization by controlling the intracellular reactive oxygen species (ROS) level through its ability to transport glutathione (a ROS scavenger) out of the cell. Moreover, we demonstrated in a mouse model that both the pharmacological inhibition and the ΔF508 mutation of CFTR lead to an impairment of the adaptive erythroid response to oxygen deprivation. We conclude that CFTR controls HIF stabilization through control of the level of intracellular ROS that act as signaling agents in the HIF-1 pathway.
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