Spaceflight suppresses inflammasome signaling and alters dopaminergic regulation in the mouse brain from Rodent Research-1 (RR-1) mission

Abstract

Abstract

Microgravity and radiation exposure during spaceflight pose significant health risks to astronauts, including disruption of physiological and neural homeostasis and increased risk of neurodegenerative disorders. Spaceflight induces neuroinflammatory responses, including inflammasome formation, which regulates innate immune signaling following cellular damage. Additionally, reduced neuromuscular activity in microgravity is associated with altered dopamine signaling. However, the direct effect on inflammasome activation and dopaminergic regulation under spaceflight is still poorly understood. In this study, we examined the genes and proteins that are associated with the inflammasome and the dopamine dysregulation associated with inflammation in mice exposed to spaceflight conditions. Mouse brains (C57BL/6J) from Rodent Research 1 (RR1, SpaceX-4) missions were analyzed based on exposure to spaceflight, simulated, and standard conditions for a baseline and control. Brain samples were analyzed for gene expression of inflammasome signaling genes and for mRNA expression to detect alterations under spaceflight conditions. Dopamine analysis was also performed to identify possible changes in major monoamines. This observation indicated that spaceflight conditions were associated with suppressed inflammasome-related gene expression with no statistically observable changes in monoamine concentration. Overall, the data established that spaceflight stressors concurrently dampen neuroinflammatory signaling while altering dopamine regulation in the brain. Inflammasome activation under internal and external signaling. (1) The spaceflight environment (Space radiation/microgravity) causes oxidative stress, and through that, (2) it activates NF-κB, which transcribes NLRP3, Pro-Caspase-1, and Pro-IL-1β. NLRP3 and Pro-Caspase-1, with the help of ASC, (3) form the Inflammasome complex, which cleaves Pro-Caspase-1 to form active Caspase-1. (4) The Active Caspase-1 activates both Pro-IL-1β and GSDMD to N-GSDMND. The N-GSDMND form a complex on the neuron cell surface and create pores, (5), allowing IL-1β and other cytokines to be released and induce pyroptosis. (6) The released cytokines act as signaling for the surface cell receptors and activate the DAMP pathways, and the cycle continues. (5 A) IL-1β also inhibits monoaminergic synthesis and decreases the amount of DA, 5-HT, and NE in the cell (6 A) and reduces the anti-inflammatory effects. DJ1 in the cell acts as a neuroprotector against oxidative stress, so it inhibits the activation of the inflammasome transcription through ROS activation. It also helps the inhibition of monoaminergic synthesis, which allows the neurotransmitters to continue their anti-inflammatory effects.