DEK deficiency suppresses mitophagy to protect against house dust mite-induced asthma
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ABSTRACT:
PROVIDER: PRJNA1018871 | ENA |
REPOSITORIES: ENA
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Project description:This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PTEN-induced putative kinase 1 (PINK1)-Parkin mediated mitophagy, NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, and apoptosis. We found that recombinant DEK protein (rmDEK) promoted eosinophils recruitment, mitochondrial fragmentation, and outer membrane 20 (TOM20) and LC3 co-localization representing mitophagosomes in bronchoalveolar lavage fluid (BALF) in house dust mite (HDM) induced-asthma. rmDEK also reduced co-localization of mitochondrial fusion protein mitofusin1 (MFN1) and mitochondria, and the protein level of manganese superoxide dismutase (MnSOD), enhanced microtubule-associated protein1 light chain 3 (LC3) and voltage-dependent anion channels (VDAC) co-localization which also represent the mitophagosomes in airway epithelial cells, furthermore, increased dynamin-related protein 1 (DRP1) expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. In the DEK knockout mice, HDM induced asthmatic airway inflammation, MnSOD, PINK1-Parkin protein level, Parkin mediated mitophagy characterized by LC3 and Parkin co-localization in the airways, ROS generation, NLRP3 inflammation and apoptosis were fully reversed. Similar effects of rmDEK were also observed in the BEAS-2B cells, which were rescued by the autophagy inhibitor 3-MA. Moreover, DEK silencing diminished the Parkin, LC3, DRP1 translocation to mitochondria; as well as mitochondrial ROS; TOM20 and mitochondrial DNA mediated mitochondrial oxidative damage. ChIP-sequence analysis showed that DEK was enriched on the AAA domain-containing protein 3A (ATAD3A) promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models. Furthermore, ATAD3A interacted with DRP1, and knockdown of ATAD3A could down-regulate DRP1 and mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.
2023-09-24 | GSE243532 | GEO
Project description:DEK protein is highly expressed in asthma. However, the mechanism of DEK on mitophagy in asthma has not been fully understood. This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. PINK1-Parkin mitophagy, NLRP3 inflammasome, and apoptosis were examined after gene silencing or treatment with specific inhibitors (MitoTEMPO, MCC950, and Ac-DEVD-CHO) in house dust mite (HDM) or recombinant DEK (rmDEK)-induced WT and DEK-/- asthmatic mice and BEAS-2B cells. The regulatory role of DEK on ATAD3A was detected using ChIP-sequence and co-immunoprecipitation. rmDEK promoted eosinophil recruitment, and co-localization of TOM20 and LC3B, MFN1 and mitochondria, LC3B and VDAC, and ROS generation, reduced protein level of MnSOD in HDM induced-asthmatic mice. Moreover, rmDEK also increased DRP1 expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. These effects were partially reversed in DEK-/- mice. In BEAS-2B cells, siDEK diminished the Parkin, LC3B, and DRP1 translocation to mitochondria, mtROS, TOM20, and mtDNA. ChIP-sequence analysis showed that DEK was enriched on the ATAD3A promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models and interacted with DRP1, and siATAD3A could down-regulate DRP1 and mtDNA-mediated mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.
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Project description:We examined the transcriptional changes in mouse lungs induced by house dust mite (HDM), D.f. extract and the isolated RNA was utilized for RNA-seq analysis. Our results demonstrated that HDM strongly triggered an inflammatory response.
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Project description:Response to allergen was studied in epithelial cells derived from allergic pantients and from healthy controls. Cells were cultured after isolation from a nasal biopsy. Cells were exposed to Housed dust mite or vessel (saline) Microarray data was analysed using bioinformatics and biostaistics. We conclude that a marked difference in basal expression and in response to hous dust mite exists Keywords: cellular response to allergen
2007-11-10 | GSE9150 | GEO
Project description:Despite robust literature associating IL-31 with pruritic inflammatory skin diseases, its influence on cutaneous inflammation and on the interplay between inflammatory and neurosensory pathways remain unmapped. Here, we examined the consequences of disrupting Il31 and its receptor Il31ra in a mouse model of house dust mite (HDM) allergic dermatitis. Il31-deficient mice displayed an increased number and proportion of cutaneous type 2 cytokine-producing CD4 T cells and serum IgE in response to HDM. Single cell RNA-sequencing analysis of skin CD45+ populations from HDM-treated skin revealed that Il4ra+ monocytes and macrophages capable of fueling a feedforward type 2 inflammatory loop were selectively enriched in Il31ra-deficient HDM dermatitis skin. Thus, IL-31 is not strictly a pro-inflammatory cytokine, but rather an immunoregulatory factor that limits the magnitude of type 2 inflammatory responses in skin.
2023-10-26 | GSE236744 | GEO
Project description:Allergic asthmatic, allergy only, asthma only (no allergy), and non-allergic non-asthmatic (control) subjects underwent bronchoscopy with instillation of saline, lipopolysaccharide (LPS), and house dust mite antigen in separate subsegmental bronchi. Airway epithelial cells were collected four hours later (three samples per subject). RNA was extracted from these cells for microarray analysis. Keywords: gene expression arrays (two-dye: sample against common "universal" reference RNA)
2009-10-01 | GSE8190 | GEO
Project description:Allergic asthmatic, allergy only, asthma only (no allergy), and non-allergic non-asthmatic (control) subjects underwent bronchoscopy with instillation of saline, lipopolysaccharide (LPS), and house dust mite antigen in separate subsegmental bronchi. Bronchoalveolar lavage (BAL) fluid was collected four hours later (three samples per subject). Inflammatory cells from each specimen were isolated and RNA was extracted for microarray analysis. Keywords: gene expression arrays (two-dye: sample against common 'universal' reference RNA)
2009-10-01 | GSE5272 | GEO
Project description:PBMC from house dust mite (HDM) sensitized atopics were cultured in the presence or absence of HDM extract for 24 hours. At the termination of the cultures, CD4 T cells were isolated using immunomagnetic separation. Gene expression was profiled on microarrays.
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Project description:Purpose: Identify whole lung gene expression patterns in a house dust mite model of mild/moderate asthma Methods: Lung gene expression profiles of 10 week old BALB/c female mice were generated by ribosome-depleted, 150 nt, paired-end, stranded RNA-seq with Illumina HiSeq v4. Sequence reads that passed quality filters after trimming were analyzed with Sailfish-cir to identify linear RNAs and circular RNAs. Differential expression of linear RNAs was assessed with Deseq2 . QRT–PCR validation was performed using TaqMan and SYBR Green methods. Results: 100 million sequence reads per sample were mapped to the mouse genome (build mm10) using Sailfish-cir to identify linear and circular RNA transcripts. Pathway analysis of differentially expressed genes identified upregulation of gene sets for human asthma, mouse lung allergic inflammation, Muc5ac regulated genes and smooth muscle genes after allergic sensitization. Gene level exppression in each asthma-related pathway was reduced by the miR-145 antagonist. The miR-145 antagonist and several nontargeting oligos also upregulated interferon signaling pathways suggesting a general antiinflammatory effect of LNA/DNA oligos in the lung. Conclusions: Lung-directed delivery of LNA/DNA oligonucleotides with cationic lipid nanoparticles is an efffective means to prevent inflammatory gene expression in a house dust mite model of mild/moderate asthma.
2019-06-06 | GSE132263 | GEO
Project description:Response to allergen was studied in epithelial cells derived from allergic pantients and from healthy controls. Cells were cultured after isolation from a nasal biopsy. Cells were exposed to Housed dust mite or vessel (saline); Microarray data was analysed using bioinformatics and biostaistics. We conclude that a marked difference in basal expression and in response to hous dust mite exists Experiment Overall Design: We used 5 monotypic house dust mite allergic patients and 5 non-allergic healthy controls, the cells obtained from the biopsies were cultured in two wells, for two different conditions.
2008-06-16 | E-GEOD-9150 | biostudies-arrayexpress