Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy
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ABSTRACT:
PROVIDER: PRJNA1004573 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25610700_1.fastq.gz | Fastqsanger.gz | |||
| SRR25610700_2.fastq.gz | Fastqsanger.gz | |||
| SRR25610701_1.fastq.gz | Fastqsanger.gz | |||
| SRR25610701_2.fastq.gz | Fastqsanger.gz | |||
| SRR25610702_1.fastq.gz | Fastqsanger.gz |
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Project description:Spaceflight-related stresses impact health via various body systems, including the hematopoietic and immune systems, with effects ranging from moderate alterations of homeostasis to serious illness. Oxidative stress appears to be involved in these changes, and the transcription factor Nrf2, which regulates expression of a set of cytoprotective and antioxidative stress response genes, has been implicated in the response to spaceflight-induced stresses. Here, we show through analyses of mice from the MHU-3 project, in which Nrf2-knockout mice travelled in space for 31 days, that mice lacking Nrf2 suffer more seriously from spaceflight-induced immunosuppression than wild-type mice. We discovered that a one-month spaceflight triggered the expression of tissue inflammatory marker genes in wild-type mice, an effect that was even more pronounced in the absence of Nrf2. Concomitant with induction of inflammatory conditions, the consumption of coagulation-fibrinolytic factors and platelets was elevated by spaceflight and further accelerated by Nrf2 deficiency. These results highlight that Nrf2 mitigates spaceflight-induced inflammation, subsequent immunosuppression, and thrombotic microangiopathy. These observations reveal a new strategy to relieve health problems encountered during spaceflight.
2023-09-14 | GSE240654 | GEO
Project description:Spaceflight-related stresses impact health via various body systems, including the haematopoietic and immune systems, with effects ranging from moderate alterations of homoeostasis to serious illness. Oxidative stress appears to be involved in these changes, and the transcription factor Nrf2, which regulates expression of a set of cytoprotective and antioxidative stress response genes, has been implicated in the response to spaceflight-induced stresses. Here, we show through analyses of mice from the MHU-3 project, in which Nrf2-knockout mice travelled in space for 31 days, that mice lacking Nrf2 suffer more seriously from spaceflight-induced immunosuppression than wild-type mice. We discovered that a one-month spaceflight-triggered the expression of tissue inflammatory marker genes in wild-type mice, an effect that was even more pronounced in the absence of Nrf2. Concomitant with induction of inflammatory conditions, the consumption of coagulation-fibrinolytic factors and platelets was elevated by spaceflight and further accelerated by Nrf2 deficiency. These results highlight that Nrf2 mitigates spaceflight-induced inflammation, subsequent immunosuppression, and thrombotic microangiopathy. These observations reveal a new strategy to relieve health problems encountered during spaceflight.
| S-EPMC10457343 | biostudies-literature
Project description:Activation of Interferon and Complement Pathways in Thrombotic Microangiopathy
| PRJNA556908 | ENA
Project description:WGS and RNA-seq data for Nrf2 study
| EGAS00001001740 | EGA
Project description:Astronauts are exposed to a unique combination of stressors during spaceflight, which leads to alterations in their physiology and potentially increases their susceptibility to infectious pathogens. Here we report the first microarray evaluation of any astronaut tissue sample, specifically whole blood, before and after spaceflight using an array comprising 234 well-characterized stress response genes. Differentially regulated genes included those important for DNA repair, oxidative stress, and protein folding/degradation. Microarrays comprising 234 well characterized stress-related genes were used to profile transcriptomic changes in six astronauts before and after short-duration spaceflight. Blood samples were collected for analysis from each eastronaut 10 days prior and 2-3 hours after return from spaceflight. Data submitted for platform GPL140 contain genes that have been pre-filtered by the analytical software to remove values of low certainty, resulting in missing values for some samples. Unfortunately, these original data are no longer available due to physical damage at Tulane University during hurricane Katrina, but the processed values were retained in redundant locations and these are submitted for upload to GEO.
2013-10-15 | E-GEOD-47126 | biostudies-arrayexpress
Project description:This study presents the first global transcriptional profiling and phenotypic characterization of the major human opportunistic fungal pathogen, Candida albicans, grown in spaceflight conditions. Microarray analysis revealed that C. albicans subjected to short-term spaceflight culture differentially regulated 454 genes compared to synchronous ground controls, which represented 8.4% of the analyzed ORFs. Spaceflight-cultured C. albicans induced genes involved in cell aggregation (similar to flocculation), which was validated by microscopic and flow cytometry analysis. We also observed enhanced random budding of spaceflight-cultured cells as opposed to more normal bipolar budding patterns for ground samples, in accordance with the gene expression data. Furthermore, genes involved in antifungal agent and stress resistance were differentially regulated in spaceflight, including induction of ABC transporters and members of the major facilitator family, downregulation of ergosterol-encoding genes, and upregulation of genes involved in oxidative stress resistance. Finally, downregulation of genes involved in the actin cytoskeleton was observed. Interestingly, the transcriptional regulator Cap1 and over 30% of the Cap1 regulon was differentially expressed in spaceflight-cultured C. albicans. A potential role for Cap1 in the spaceflight response of C. albicans is suggested, as this regulator is involved in random budding, cell aggregation, actin cytoskeleton, and oxidative stress resistance; all related to observed spaceflight-associated changes of C. albicans. While culture of C. albicans in microgravity potentiates a global change in gene expression that could induce a virulence-related phenotype, no increased virulence in a murine intraperitoneal (i.p.) infection model was observed. This study represents an important basis for the assessment of the risk that commensal flora could play during spaceflight missions. Furthermore, since the low fluid-shear environment of microgravity is relevant to physical forces encountered by pathogens during the infection process, insights gained from this study could identify novel infectious disease mechanisms, with downstream benefits for the general public. Cells were grown for 24 hours on the space shuttle or as ground-based controls, preserved in RNALater, and stored at -80C. Four samples of each flight- and ground-based controls were harvested for microarray analysis. GAP is Group Activation Pack and each GAP contains 8 FPAs. The numbers represent the # assigned to the particular GAP and the number assigned to the specific FPA (1-8) within the indicated GAP. The same hardware is used for the flight samples and the ground samples.
2013-11-01 | E-GEOD-50881 | biostudies-arrayexpress
Project description:Metabolic regulation recently emerged as a novel powerful principle guiding immune responses. The natural metabolite itaconate and its membrane permeable derivative dimethyl itaconate (DI) were recently shown to selectively inhibit a subset of cytokines during macrophage activation, yet the precise mechanism of this effect remained unclear. We show here that itaconate/DI react with glutathione and subsequently induce both Nrf2-dependent and Nrf2-independent stress responses. We find that the striking selectivity of DI action stems from the inhibitory effects of electrophilic stress on IKBZ protein translation, leading to the inhibition of only the secondary wave of NF-KB signaling. We find that IKBZ regulation occurs in an Nrf2-independent manner, and identify ATF3 as a key mediator of the immunosuppression.
2018-02-25 | MSV000082101 | MassIVE
Project description:Transplant-associated thrombotic microangiopathy (TA-TMA) is a significant cause of mortality after hematopoietic stem cell transplant (HSCT). Complement blockade is an effective therapeutic strategy for TA-TMA, but some patients with severe disease lack a complete response, prompting a search for additional targetable endothelial injury pathways. We performed transcriptome analysis of peripheral blood mononuclear cells collected prior to HSCT and at onset of TA-TMA and observed significant up-regulation of classical and alternative complement pathways during active TA-TMA. At resolution of TA-TMA after eculizumab therapy, essentially all up-regulated genes and pathways returned to baseline expression levels, supporting the clinical practice of successfully discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling. To confirm our observations, we documented a high incidence of clinically significant TMA in children with hemophagocytic lymphohistiocytosis (HLH), an interferon gamma-driven disease, outside the setting of transplantation. We also confirmed increased interferon signaling in a separate cohort of patients by measuring CXCL9 and CXCL10 in urine. Our data suggest a key relationship between increased interferon signaling, complement activation, and TMA in two distinct clinical settings, HLH and TA-TMA. Combined anti-complement and anti-interferon treatment may facilitate disease control in patients with refractory TA-TMA. These data cast light on the occurrence of TMA in persons receiving therapeutic interferons, and possibility of TMA in other interferon-driven diseases where interferon may be a novel therapeutic target.
2020-03-30 | GSE134979 | GEO
Project description:This study presents the first global transcriptional profiling and phenotypic characterization of the major human opportunistic fungal pathogen, Candida albicans, grown in spaceflight conditions. Microarray analysis revealed that C. albicans subjected to short-term spaceflight culture differentially regulated 454 genes compared to synchronous ground controls, which represented 8.4% of the analyzed ORFs. Spaceflight-cultured C. albicans induced genes involved in cell aggregation (similar to flocculation), which was validated by microscopic and flow cytometry analysis. We also observed enhanced random budding of spaceflight-cultured cells as opposed to more normal bipolar budding patterns for ground samples, in accordance with the gene expression data. Furthermore, genes involved in antifungal agent and stress resistance were differentially regulated in spaceflight, including induction of ABC transporters and members of the major facilitator family, downregulation of ergosterol-encoding genes, and upregulation of genes involved in oxidative stress resistance. Finally, downregulation of genes involved in the actin cytoskeleton was observed. Interestingly, the transcriptional regulator Cap1 and over 30% of the Cap1 regulon was differentially expressed in spaceflight-cultured C. albicans. A potential role for Cap1 in the spaceflight response of C. albicans is suggested, as this regulator is involved in random budding, cell aggregation, actin cytoskeleton, and oxidative stress resistance; all related to observed spaceflight-associated changes of C. albicans. While culture of C. albicans in microgravity potentiates a global change in gene expression that could induce a virulence-related phenotype, no increased virulence in a murine intraperitoneal (i.p.) infection model was observed. This study represents an important basis for the assessment of the risk that commensal flora could play during spaceflight missions. Furthermore, since the low fluid-shear environment of microgravity is relevant to physical forces encountered by pathogens during the infection process, insights gained from this study could identify novel infectious disease mechanisms, with downstream benefits for the general public.
2013-11-01 | GSE50881 | GEO
Project description:Spaceflight triggers molecular signal of apoptosis and inhibits cell migration to impede bone fracture repair in male mice Activated apoptosis and inhibited cell migration. Adverse impacts of spaceflight on musculoskeletal health increases the risk of bone fracture and impaired healing. Its yet elusive molecular comprehension warrants an immediate attention in the advent of increasingly frequent space travels. Here we examined the effect of spaceflight on bone healing using a 2mm femoral segmental bone defect (SBD) model. Forty, 9-week old, C57BL/6J male mice were randomized by cage into spaceflight or ground groups; 10 mice from spaceflight or ground groups, respectively underwent SBD surgery and rest served as unoperated sham controls. Surgery/sham procedures occurred 4 days prior to launch, thereafter the spaceflight mice were housed in the rodent habitat at International Space Station for around 4 weeks before their euthanasia. Feeding on same diet, the ground sham/surgery mice were in equivalent housing condition. The right leg femur from half of the spaceflight and ground groups were investigated by micro-computed tomography (µCT). In parallel, the callus regions from surgery groups and corresponding femoral segments in sham mice were probed by global transcriptomics and metabolomics assay. µCT confirmed escalated bone loss in sham spaceflight; and a concomitant trend towards habituation was highlighted by gene-metabolite networks linked to active cellular homeostasis and inhibited morbidity signal in sham spaceflight. The morbidity signal was switched in the spaceflight surgery mice and µCT analyses of spaceflight callus revealed an increased trabeculae spacing and decreased trabecular connectivity. Activated apoptotic signal in spaceflight callus was synchronized with inhibited cell migration signal that was critical for wounds to recruit growth factors, cytokines, and angiogenic agents. A major pro-apoptotic and anti-migration signal, namely RANK-NFκB axis emerged as the central node in spaceflight callus. Concluding, SBD in spaceflight triggered a unique biomolecular mechanism to meet failed regeneration, which merits a customized intervention strategy.
2021-06-30 | GSE161618 | GEO