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Lack of Fzd6 in Ciliated Cells Suppresses Ferroptotic Alveolar Cell Death induced by LPS and Corona Virus [RNA-seq subset I]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE221068 | GEO | 2023/01/31

REPOSITORIES: GEO

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Lack of Fzd6 in Ciliated Cells Suppresses Ferroptotic Alveolar Cell Death induced by LPS and Corona Virus [RNA-seq subset II]

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

Effects of Myb shRNA on Airway Epithelial Cells

Project description:The epithelium of the pulmonary airway is specially differentiated to provide defense against environmental insults, but also subject to dysregulated differentiation that results in lung disease. The current paradigm for airway epithelial differentiation is a one-step program whereby a p63+ basal epithelial progenitor cell generates a ciliated or secretory cell lineage, but the cue for this transition and whether there are intermediate steps is poorly defined. Here we identify transcription factor Myb as a key regulator that permits early multilineage differentiation of airway epithelial cells. Myb+ cells were identified as p63– and therefore distinct from basal progenitor cells, but were still negative for markers of differentiation. Myb RNAi treatment of primary-culture airway epithelial cells and Myb gene deletion in mice resulted in a p63– population with failed maturation of Foxj1+ ciliated cells, as well as Scbg1a1+ and Muc5ac+ secretory cells. Consistent with these findings, analysis of whole genome expression of Myb-deficient cells identified Myb-dependent programs for ciliated and secretory cell differentiation. Myb+ cells were rare in human airways but were increased in regions of ciliated cells and mucous cell hyperplasia in samples from subjects with chronic obstructive pulmonary disease. Together, the results show that a p63– Myb+ population of airway epithelial cells represents a distinct intermediate stage of differentiation that is required under normal conditions and may be heightened in airway disease. 12 samples, 2x2 factorial design, factor 1: time (days post-ALI), factor 2:shRNA (Myb vs Scrambled Control), performed in triplicate (biological replicates)

2014-08-12 | E-GEOD-60365 | biostudies-arrayexpress

Effects of Myb shRNA on Airway Epithelial Cells

2014-08-12 | GSE60365 | GEO

Targeted alveolar regeneration with Frizzled-specific agonists

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2023-06-16 | GSE208770 | GEO

Deep spatial proteomics reveals region-specific features of severe COVID-19-related pulmonary injury

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2024-01-22 | PXD043807 | Pride

Identification of FOXJ1 effectors during ciliogenesis in the fetal respiratory epithelium and embryonic left-right organizer of the mouse - Lung subscreen B

Project description:Formation of motile cilia in vertebrate embryos is essential for proper development and tissue function. Key regulators of motile ciliogenesis are the transcription factors FOXJ1 and NOTO, which are conserved throughout vertebrates. Downstream target genes of FOXJ1 have been identified in a variety of species, organs and cultured cell lines; in murine embryonic and foetal tissues, however, FOXJ1 and NOTO effectors have not been comprehensively analysed and our knowledge of the downstream genetic programme driving motile ciliogenesis in the mammalian lung and ventral node is fragmentary. We compared genome-wide expression profiles of undifferentiated E14.5 vs. abundantly ciliated E18.5 micro-dissected airway epithelia as well as Foxj1+ vs. Foxj1-deficient foetal (E16.5) lungs of the mouse using microarray hybridisation. 326 genes deregulated in both screens are candidates for FOXJ1-dependent, ciliogenesis-associated factors at the endogenous onset of motile ciliogenesis in the lung, including 123 genes that have not been linked to ciliogenesis before; 46% of these novel factors lack known homologues outside mammals. Microarray screening of Noto+ vs. Noto null early headfold embryos (E7.75) identified 59 of the lung candidates as NOTO/FOXJ1-dependent factors in the embryonic left-right organiser that carries a different subtype of motile cilia. For several uncharacterised factors from this small overlap – including 1700012B09Rik, 1700026L06Rik and Fam183b – we provide extended experimental evidence for a ciliary function.

2017-09-18 | GSE89582 | GEO

Identification of FOXJ1 effectors during ciliogenesis in the fetal respiratory epithelium and embryonic left-right organizer of the mouse - Lung subscreen A

2017-09-18 | GSE89581 | GEO

Identification of FOXJ1 effectors during ciliogenesis in the fetal respiratory epithelium and embryonic left-right organizer of the mouse - IMCD3 screen

2017-09-18 | GSE89584 | GEO

Identification of FOXJ1 effectors during ciliogenesis in the fetal respiratory epithelium and embryonic left-right organizer of the mouse - Noto screen

2017-09-18 | GSE89583 | GEO

Activation of SREBP in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity

Project description:Background: Lung function is dependent upon the precise regulation of the synthesis, storage, and catabolism of tissue and alveolar lipids. Results: Activation of SREBP (Sterol Response Element Binding Protein) induced lipogenesis in alveolar epithelial cells, causing neutral lipid accumulation, lung inflammation, and tissue remodeling. Conclusions: The accumulation of neutral lipids in type II epithelial cells and alveolar macrophages caused lung inflammation, consistent with findings in lipid storage disorders. Significance: Pulmonary lipotoxicity may contribute to the pathogenesis of lung dysfunction associated with diabetes, obesity, and other metabolic disorders. Genome-wide transcription profiling comparison between doxycycline-exposed SFTPC-rtTAWT/Tg/(tetO)7CMV-CreWT/Tg/Insig1flox/flox/Insig2-/- mice (i.e., Insig1/2∆/∆ ) and Insig1flox/flox/Insig2-/- . Three independent pooled RNA from isolated lung type 2 cells of each genotype were used.

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