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Project description:Pulmonary inflammation compromises lung barrier function and underlies many lung diseases including acute lung injury and acute respiratory distress syndrome (ARDS). However, mechanisms by which lung cells respond to the damage caused by the inflammatory insults are not completely understood. Here we show that Fzd6-deficiency in Foxj1+ ciliated cells reduces pulmonary permeability, lipid peroxidation, and alveolar cell death accompanied with an increase in alveolar number in lungs insulted by LPS or mouse coronavirus MHV-1. Single cell RNA sequencing of lung cells indicates that the lack of Fzd6, which is primarily expressed in Foxj1+ ciliated cells, increases expression of the aldo-keto reductase Akr1b8. Intratracheal administration of the Akr1b8 protein phenocopies Fzd6-deficient lung phenotypes. In addition, ferroptosis inhibitors also phenocopy Fzd6-deficient lung phenotypes and exert no further effects in Fzd6-deficient lungs. These results indicate that Fzd6-deficiency suppresses inflammation-induced ferroptotic death of alveolar cells via the release of Akr1b8, thus revealing a previously unknown mechanism by which Fzd6 signaling regulates ferroptosis via a paracrine pathway. In addition, this study demonstrates the yet-to-be appreciated importance of ciliated cells in protecting alveolar cells during pulmonary inflammation.
2023-01-31 | GSE222753 | GEO
Project description:Pulmonary inflammation compromises lung barrier function and underlies many lung diseases including acute lung injury and acute respiratory distress syndrome (ARDS). However, mechanisms by which lung cells respond to the damage caused by the inflammatory insults are not completely understood. Here we show that Fzd6-deficiency in Foxj1+ ciliated cells reduces pulmonary permeability, lipid peroxidation, and alveolar cell death accompanied with an increase in alveolar number in lungs insulted by LPS or mouse coronavirus MHV-1. Single cell RNA sequencing of lung cells indicates that the lack of Fzd6, which is primarily expressed in Foxj1+ ciliated cells, increases expression of the aldo-keto reductase Akr1b8. Intratracheal administration of the Akr1b8 protein phenocopies Fzd6-deficient lung phenotypes. In addition, ferroptosis inhibitors also phenocopy Fzd6-deficient lung phenotypes and exert no further effects in Fzd6-deficient lungs. These results indicate that Fzd6-deficiency suppresses inflammation-induced ferroptotic death of alveolar cells via the release of Akr1b8, thus revealing a previously unknown mechanism by which Fzd6 signaling regulates ferroptosis via a paracrine pathway. In addition, this study demonstrates the yet-to-be appreciated importance of ciliated cells in protecting alveolar cells during pulmonary inflammation.
2023-01-31 | GSE221068 | GEO
Project description:Lack of Fzd6 in Ciliated Cells Suppresses Ferroptotic Alveolar Cell Death induced by LPS and Corona Virus
| PRJNA923597 | ENA
Project description:Lack of Fzd6 in Ciliated Cells Suppresses Ferroptotic Alveolar Cell Death induced by LPS and Corona Virus [RNA-seq subset II]
| PRJNA923317 | ENA
Project description:Lack of Fzd6 in Ciliated Cells Suppresses Ferroptotic Alveolar Cell Death induced by LPS and Corona Virus [RNA-seq subset I]
| PRJNA912699 | ENA
Project description:BackgroundDespite an increasing understanding of chronic obstructive pulmonary disease (COPD) pathogenesis, the mechanisms of diverse cell populations in the human lung remain unknown. Using single-cell RNA sequencing (scRNA-Seq), we can reveal changes within individual cell populations in COPD that are important for disease pathogenesis and characteristics.MethodsWe performed scRNA-Seq on lung tissue obtained from donors with non-COPD and mild-to-moderate COPD to identify disease-related genes within different cell types. We testified the findings using qRT-PCR, immunohistochemistry, immunofluorescence and Western blotting from 25 additional subjects and RAW 264.7 macrophages. Targeting ferroptosis with the ferroptosis inhibitor ferrostatin-1, iron chelator deferoxamine or HO-1 inhibitor zinc protoporphyrin was administered in the experimental cigarette smoke COPD mouse model.ResultsWe identified two populations of alveolar macrophages (AMs) in the human lung that were dysregulated in COPD patients. We discovered that M2-like AMs modulate susceptibility to ferroptosis by disrupting lipid and iron homeostasis both in vivo and in vitro. The discrepancy in sensitivity to ferroptosis can be determined and regulated by HO-1. In contrast, M1-like AMs showed the ability to attenuate oxidative stress and exert resistance to ferroptosis. In addition, the expression of genes within M2-like AMs is also involved in defects in phagocytosis and lysosome distortion. This ferroptotic phenotype was ameliorated by antiferroptotic compounds, iron chelators and HO-1 inhibitors. During COPD, the accumulation of lipid peroxidation drives ferroptosis-sensitive M2-like AMs, while M1-like AMs show characteristics of ferroptosis resistance. Ferroptotic M2 AMs lose their anti-inflammatory and repair functions but provoke inflammatory responses, resulting in consistent inflammation and tissue damage in the presence of M1 AMs in COPD.ConclusionAppropriate interventions in ferroptosis can reduce the occurrence of infections and acute onset, and delay the COPD process.
| S-EPMC10196003 | biostudies-literature
Project description:Caspase-2, one of the most evolutionarily conserved members of the caspase family, is an important regulator of the cellular response to oxidative stress. Given that ferroptosis is suppressed by antioxidant defense pathways, such as that involving selenoenzyme glutathione peroxidase 4 (GPX4), we hypothesized that caspase-2 may play a role in regulating ferroptosis. This study provides the first demonstration of an important and unprecedented function of caspase-2 in protecting cancer cells from undergoing ferroptotic cell death. Specifically, we show that depletion of caspase-2 leads to the downregulation of stress response genes including SESN2, HMOX1, SLC7A11, and sensitizes mutant-p53 cancer cells to cell death induced by various ferroptosis-inducing compounds. Importantly, the canonical catalytic activity of caspase-2 is not required for its role and suggests that caspase-2 regulates ferroptosis via non-proteolytic interaction with other proteins. Using an unbiased BioID proteomics screen, we identified novel caspase-2 interacting proteins (including heat shock proteins and co-chaperones) that regulate cellular responses to stress. Finally, we demonstrate that caspase-2 limits chaperone-mediated autophagic degradation of GPX4 to promote the survival of mutant-p53 cancer cells. In conclusion, we document a novel role for caspase-2 as a negative regulator of ferroptosis in cells with mutant p53. Our results provide evidence for a novel function of caspase-2 in cell death regulation and open potential new avenues to exploit ferroptosis in cancer therapy.
| S-EPMC10907636 | biostudies-literature
Project description:Ca2+ activated Cl- channels (TMEM16A; ANO1) support cell proliferation and cancer growth. Expression of TMEM16A is strongly enhanced in different types of malignomas. In contrast, TMEM16F (ANO6) operates as a Ca2+ activated chloride/nonselective ion channel and scrambles membrane phospholipids to expose phosphatidylserine at the cell surface. Both phospholipid scrambling and cell swelling induced through activation of nonselective ion currents appear to destabilize the plasma membrane thereby causing cell death. There is growing evidence that activation of TMEM16F contributes to various forms of regulated cell death. In the present study, we demonstrate that ferroptotic cell death, occurring during peroxidation of plasma membrane phospholipids activates TMEM16F. Ferroptosis was induced by erastin, an inhibitor of the cystine-glutamate antiporter and RSL3, an inhibitor of glutathione peroxidase 4 (GPX4). Cell death was largely reduced in the intestinal epithelium, and in peritoneal macrophages isolated from mice with tissue-specific knockout of TMEM16F. We show that TMEM16F is activated during erastin and RSL3-induced ferroptosis. In contrast, inhibition of ferroptosis by ferrostatin-1 and by inhibitors of TMEM16F block TMEM16F currents and inhibit cell death. We conclude that activation of TMEM16F is a crucial component during ferroptotic cell death, a finding that may be useful to induce cell death in cancer cells.
| S-EPMC6562394 | biostudies-literature
Project description:Ferroptosis is a caspase-independent form of regulated cell death strongly linked to the accumulation of reactive lipid hydroperoxides. Lipid hydroperoxides are neutralized in cells by glutathione peroxidase 4 (GPX4) and inhibitors of GPX4 are potent ferroptosis inducers with therapeutic potential in cancer. Here we report that siRNA-mediated silencing of the AMPK-related kinase NUAK2 suppresses cell death by small-molecule inducers of ferroptosis but not apoptosis. Mechanistically we find that NUAK2 suppresses the expression of GPX4 at the RNA level and enhances ferroptosis triggered by GPX4 inhibitors in a manner independent of its kinase activity. NUAK2 is amplified along with MDM4 in a subset of breast cancers, particularly the claudin-low subset, suggesting that this may predict vulnerability to GPX4 inhibitors. These findings identify a novel pathway regulating GPX4 expression as well as ferroptotic sensitivity with potential as a biomarker of breast cancer patients that might respond to GPX4 inhibition as a therapeutic strategy.
| S-EPMC9076840 | biostudies-literature
Project description:Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death.
| S-EPMC4076414 | biostudies-literature