Adenosine A2A receptor modulates the oxidative stress response of primed polymorphonuclear leukocytes after parabolic flight

Gravitational stress in general and microgravity (µg) in particular are regarded as major stress factors responsible for immune system dysfunction in space. To assess the effects of alternating µg and hypergravity (hyper-g) on immune cells, the attachment of peripheral blood mononuclear cells (PBMCs) to adhesion molecules under flow conditions and the antigen-induced immune activation in whole blood were investigated in parabolic flight (PF). In contrast to hyper-g (1.8 g) and control conditions (1 g), flow and rolling speed of PBMCs were moderately accelerated during µg-periods which were accompanied by a clear reduction in rolling rate. Whole blood analyses revealed a “primed” state of monocytes after PF with potentiated antigen-induced pro-inflammatory cytokine responses. At the same time, concentrations of anti-inflammatory cytokines were increased and monocytes displayed a surface molecule pattern that indicated immunosuppression. The results suggest an immunologic counterbalance to avoid disproportionate immune responses. Understanding the interrelation of immune system impairing and enhancing effects under different gravitational conditions may support the design of countermeasures to mitigate immune deficiencies in space.

Section: Discussionmentioning

confidence: 99%

Cells´ Flow and Immune Cell Priming under alternating g-forces in Parabolic Flight

Moser¹,

Sun

et al. 2019

“…The presence of an altered metabolic condition and/or oxidative stress and mitochondrial dysfunction has been documented in many in vivo and in vitro models exposed to real or simulated microgravity. The presence of many oxidative stress markers has been reported in blood from cosmonauts and pilots experiencing routine or short-term gravitational changes 48 , 49 . Similar effects on an increase in ROS production and metabolic unbalance were observed in vivo and in vitro in different models subjected to s-microgravity conditions.…”

Section: Discussionmentioning

confidence: 99%

Transient increases in intracellular calcium and reactive oxygen species levels in TCam-2 cells exposed to microgravity

Morabito

Guarnieri

Catizone

et al. 2017

The effects of microgravity on functions of the human body are well described, including alterations in the male and female reproductive systems. In the present study, TCam-2 cells, which are considered a good model of mitotically active male germ cells, were used to investigate intracellular signalling and cell metabolism during exposure to simulated microgravity, a condition that affects cell shape and cytoskeletal architecture. After a 24 hour exposure to simulated microgravity, TCam-2 cells showed 1) a decreased proliferation rate and a delay in cell cycle progression, 2) increased anaerobic metabolism accompanied by increased levels of intracellular Ca2+, reactive oxygen species and superoxide anion and modifications in mitochondrial morphology. Interestingly, all these events were transient and were no longer evident after 48 hours of exposure. The presence of antioxidants prevented not only the effects described above but also the modifications in cytoskeletal architecture and the activation of the autophagy process induced by simulated microgravity. In conclusion, in the TCam-2 cell model, simulated microgravity activated the oxidative machinery, triggering transient macroscopic cell events, such as a reduction in the proliferation rate, changes in cytoskeleton-driven shape and autophagy activation.

“…The switch from micro- to hypergravity conditions also potentiated antigen-induced immune cell activation and cytokine secretion 10 . This “priming,” i.e., increased sensitivity to stimuli, was demonstrated in a series of parabolic flight experiments with polymorphonuclear leukocytes 11 , 12 . Therefore, studying the combination of gravity changes and cellular hypoxia consequences is an important topic for aerospace medicine.…”

Section: Introductionmentioning

confidence: 80%

Expression of hypoxia-inducible genes is suppressed in altered gravity due to impaired nuclear HIF1α accumulation

Aboouf,

Thiel,

Borisov

et al. 2023

Extravehicular activities, the backbone of manned space exploration programs, set astronauts into mild hypoxia. Unfortunately, microgravity aggravates threatening symptoms of hypoxia such as vision impairment and brain edema. Hypoxia-inducible factors (HIFs) sense cellular hypoxia and, subsequently, change the cells’ expression profile instantaneously by rapidly translocating—most likely cytoskeleton-dependently—into the nucleus and subsequently forming transcription complexes with other proteins. We tested the hypothesis that this fundamental process could be altered by sudden changes in gravitational forces in parabolic flights using a newly developed pocket-size cell culture lab that deoxygenizes cells within 15 min. Sudden gravity changes (SGCs 1g–1.8g–0g–1.8g–1g) during hypoxic exposure suppressed expression of the HIF1α-dependent genes investigated as compared with hypoxia at constant 1g. Normoxic cells subjected to SGCs showed reduced nuclear but not cytoplasmatic HIF1α signal and appeared to have disturbed cytoskeleton architecture. Inhibition of the actin-dependent intracellular transport using a combination of myosin V and VI inhibitors during hypoxia mimicked the suppression of the HIF1α-dependent genes observed during hypoxic exposure during SGCs. Thus, SGCs seem to disrupt the cellular response to hypoxia by impairing the actin-dependent translocation of HIF1α into the nucleus.