Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity

Abstract

The immune system is one of the most affected systems of the human body during space flight. The cells of the immune system are exceptionally sensitive to microgravity. Thus, serious concerns arise, whether space flight associated weakening of the immune system ultimately precludes the expansion of human presence beyond the Earth's orbit. For human space flight, it is an urgent need to understand the cellular and molecular mechanisms by which altered gravity influences and changes the functions of immune cells. The CELLBOX-PRIME (= CellBox-Primary Human Macrophages in Microgravity Environment) experiment investigated for the first time microgravity-associated long-term alterations in primary human macrophages, one of the most important effector cells of the immune system. The experiment was conducted in the U.S. National Laboratory on board of the International Space Station ISS using the NanoRacks laboratory and Biorack type I standard CELLBOX EUE type IV containers. Upload and download were performed with the SpaceX CRS-3 and the Dragon spaceship on April 18th, 2014 / May 18th, 2014. Surprisingly, primary human macrophages exhibited neither quantitative nor structural changes of the actin and vimentin cytoskeleton after 11 days in microgravity when compared to 1g controls. Neither CD18 or CD14 surface expression were altered in microgravity, however ICAM-1 expression was reduced. The analysis of 74 metabolites in the cell culture supernatant by GC–TOF–MS, revealed eight metabolites with significantly different quantities when compared to 1g controls. In particular, the significant increase of free fucose in the cell culture supernatant was associated with a significant decrease of cell surface–bound fucose. The reduced ICAM-1 expression and the loss of cell surface–bound fucose may contribute to functional impairments, e.g. the activation of T cells, migration and activation of the innate immune response. We assume that the surprisingly small and non-significant cytoskeletal alterations represent a stable “steady state” after adaptive processes are initiated in the new microgravity environment. Due to the utmost importance of the human macrophage system for the elimination of pathogens and the clearance of apoptotic cells, its apparent robustness to a low gravity environment is crucial for human health and performance during long-term space missions.

Modeling the Impact of Microgravity at the Cellular Level: Implications for Human Disease

“…Numerous studies have been conducted on a myriad of cell types highlighting morphological sensitivity to microgravity (Ingber, 1999;Vorselen et al, 2014), with the first documented morphological change reported by Rijken et al (1991). Morphological changes as a result of microgravity conditions, either real or simulated, have been shown to have altered transcription, translation, and organization of cytoskeletal proteins (Vassy et al, 2001;Infanger et al, 2006b;Tauber et al, 2017). Fundamental work carried out by Tabony, Pochon, and Papaseit showed that while tubulin self-assembly into microtubules occurs independent of gravity, the assembly and organization of the microtubule network is gravity dependent (Papaseit et al, 2000;Tabony et al, 2002).…”

“…Osteosarcoma cells (ROS 17/2.8) Cell morphological change to rounded shape with long cytoplasmic extensions 4 days and 6 days Guignandon et al, 1997 Osteosarcoma cells (ROS 17/2.8) Reduction in cell spread area and vinculin spot area, actin and focal adhesion, and stress fibers 12 and 24 h Guignandon et al, 2003 Breast cancer (MCF-7) Disoriented microtubule 1.5 h Vassy et al, 2003 Thyroid cancer (ML-1) Actin fiber reorganization Parabola flight Ulbrich et al, 2011 Human macrophages No effect on cytoskeletal structure 11 days Tauber et al, 2017 Human chondrocytes Effect on cell cytoplasm, microtubule network disruption, loss of stress fibers, actin fiber reorganization.…”

Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFκB and metabolic pathways

“…8 Together, data from the International Space Station, Skylab, and space shuttle suggest that dysregulated immune cell-mediated cytokine secretion is a major mechanism leading to spaceflightassociated immune dysfunction. 5,[9][10][11][12] For example, after space travel, shifts occur in circulating cytokines, including increased levels of T lymphocytes producing IL-4, IL-8, IL-17, and IFN-γ 8,13,14 and decreased production of IL-1, IL-6, IL-12, and TNF-α in monocytes/ macrophages. [15][16][17][18] However, the causes of these immune cell dysfunctions and the associated changes in innate (macrophages and NK cells) and adaptive (T-cell) functions have not been extensively and systematically examined.…”

Schnelle zelluläre Reaktion und Anpassung an Schwerelosigkeit

“…In unseren Studien untersuchten wir Signaltransduktionskaskaden [3,[6][7][8], Adhäsionsmoleküle [9][10][11], Stoffwechsel [11], funktionelle Parameter [12,13], Genexpressionsreaktionen [6,[14][15][16][17][18][19]…”