Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy

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. Overall design: In the MHU-3 project, we prepared wild-type (WT) male mice and Nrf2-KO male mice, and these mice went to spaceflight for 31 days. After spaceflight, we obtained samples, including bone marrow cells as cryopreserved cells in CELLBANKER2 (Nippon Zenyaku Kougyo). We prepared the RNA samples from the cryopreserved bone marrow cells of space-flew WT mice (FW, n = 6), space-flew Nrf2-KO mice (FN, n = 6), ground-control WT mice (GW, n = 6) and ground-control Nrf2-KO mice by ISOGEN-LS (NIPPON GENE). The cDNA libraries for RNA-sequencing were prepared by MGIEasy RNA Directional Library Prep Set (MGI). The libraries were sequenced using DNBSEQ-G400 (MGI).