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Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE240654 | GEO | 2023/09/14

REPOSITORIES: GEO

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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.

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Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy

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