May the Force Be with You (Or Not): The Immune System under Microgravity (original) (raw)
Related papers
Mechano-Immunomodulation in Space: Mechanisms Involving Microgravity-Induced Changes in T Cells
Life
Of the most prevalent issues surrounding long-term spaceflight, the sustainability of human life and the maintenance of homeostasis in an extreme environment are of utmost concern. It has been observed that the human immune system is dysregulated in space as a result of gravitational unloading at the cellular level, leading to potential complications in astronaut health. A plethora of studies demonstrate intracellular changes that occur due to microgravity; however, these ultimately fall short of identifying the underlying mechanisms and dysfunctions that cause such changes. This comprehensive review covers the changes in human adaptive immunity due to microgravity. Specifically, there is a focus on uncovering the gravisensitive steps in T cell signaling pathways. Changes in gravitational force may lead to interrupted immune signaling cascades at specific junctions, particularly membrane and surface receptor-proximal molecules. Holistically studying the interplay of signaling with m...
Macrophages in microgravity: the impact of space on immune cells
NPJ Microgravity, 2021
The effects of a microgravity environment on the myriad types of immune cells present within the human body have been assessed both by bench-scale simulation and suborbital methods, as well as in true spaceflight. Macrophages have garnered increased research interest in this context in recent years. Their functionality in both immune response and tissue remodeling makes them a unique cell to investigate in regards to gravisensitive effects as well as parameters of interest that could impact astronaut health. Here, we review and summarize the literature investigating the effects of microgravity on macrophages and monocytes regarding the microgravity environment simulation/generation methods, cell sources, experiment durations, and parameters of interest utilized within the field. We discuss reported findings on the impacts of microgravity on macrophage/monocyte structure, adhesion and migration, proliferation, genetic expression, cytokine secretion, and reactive oxygen species produc...
Human immune system adaptations to simulated microgravity revealed by single-cell mass cytometry
Scientific Reports, 2021
Exposure to microgravity (µG) during space flights produces a state of immunosuppression, leading to increased viral shedding, which could interfere with long term missions. However, the cellular mechanisms that underlie the immunosuppressive effects of µG are ill-defined. A deep understanding of human immune adaptations to µG is a necessary first step to design data-driven interventions aimed at preserving astronauts' immune defense during short-and long-term spaceflights. We employed a high-dimensional mass cytometry approach to characterize over 250 cell-specific functional responses in 18 innate and adaptive immune cell subsets exposed to 1G or simulated (s) µG using the Rotating Wall Vessel. A statistically stringent elastic net method produced a multivariate model that accurately stratified immune responses observed in 1G and sµG (p value 2E−4, crossvalidation). Aspects of our analysis resonated with prior knowledge of human immune adaptations to µG, including the dampening of Natural Killer, CD4 + and CD8 + T cell responses. Remarkably, we found that sµG enhanced STAT5 signaling responses of immunosuppressive T regs. Our results suggest µG exerts a dual effect on the human immune system, simultaneously dampening cytotoxic responses while enhancing T reg function. Our study provides a single-cell readout of sµG-induced immune dysfunctions and an analytical framework for future studies of human immune adaptations to human long-term spaceflights. During spaceflight, suppression of the immune system is a well-documented consequence of both short-and long-duration missions 1-9. The dysregulation of immunological mechanisms have been studied in ground simulations of microgravity (µG) 8-11 , in human immune cells 4,12,13 and in mice (astromice) 8,9 during spaceflight, and in astronauts 9,12,14,15. Transcriptomic analyses of human peripheral blood mononuclear cells (PBMCs), splenocytes and purified T cells activated in µG during spaceflight have demonstrated that the absence of gravity profoundly inhibits the capacity of immune cells to respond to in-vivo 8 and ex-vivo stimulations 8,9,12,14,15. Evidence of enhanced virulence of pathogens 16,17 and increased viral shedding in astronauts exposed to µG presents potential mission-critical risks for long-duration, deep space exploration 18-20. Emerging high-content, immune-profiling technologies, including mass cytometry, provide powerful means for the single-cell evaluation of complex physiological immune responses, such as that produced by µG 9,11-15,21-24. Here, we utilized a 41-parameter mass cytometry approach to comprehensively profile the effect of µG on human PBMC surface activation markers and intracellular signaling responses, cultured in the NASA developed Rotating Wall Vessel, one of the most commonly used models of simulated (s)µG 25,26. Other established sµG models include the two-dimensional clinorotation and the Random Positioning Machine models 9,27-31. The primary goal of the study was to expand current knowledge anchored in bulk transcriptomic profiles of PBMCs 4,12,14,15
Scientific Reports, 2016
Microgravity is a prominent health hazard for astronauts, yet we understand little about its effect at the molecular systems level. In this study, we have integrated a set of systems-biology tools and databases and have analysed more than 8000 molecular pathways on published global gene expression datasets of human cells in microgravity. Hundreds of new pathways have been identified with statistical confidence for each dataset and despite the difference in cell types and experiments, around 100 of the new pathways are appeared common across the datasets. They are related to reduced inflammation, autoimmunity, diabetes and asthma. We have identified downregulation of NfκB pathway via Notch1 signalling as new pathway for reduced immunity in microgravity. Induction of few cancer types including liver cancer and leukaemia and increased drug response to cancer in microgravity are also found. Increase in olfactory signal transduction is also identified. Genes, based on their expression pattern, are clustered and mathematically stable clusters are identified. The network mapping of genes within a cluster indicates the plausible functional connections in microgravity. This pipeline gives a new systems level picture of human cells under microgravity, generates testable hypothesis and may help estimating risk and developing medicine for space missions. The future plan of manned mission to Mars and asteroids 1 requires astronauts to spend years in space. Microgravity is one of the most prominent health hazards for astronauts 2,3. During today's space missions, a short to moderate microgravity exposure (days to months) induces several physiological changes in human body including bone and muscle loss, puffiness in the face, change in cardiovascular physiology, catecholamine cardiomyopathy, insufficient blood flow in the brain, genitourinary issues and disturbance in neurovestibular system 2-7. Further, microgravity induces deregulation of human immune systems 8,9. Multiple gene expression studies showed microgravity-induced signature of early inhibition in T cell activation 10 , impaired endothelial cell function 11 , cellular senescence 12 , alteration of genes related to cell cycle 13,14 , cell adhesion 11 , oxidative phosphorylation 14 and apoptosis 14. It has been showed that the reduced immunity may result from inhibition of NF-κB/Rel pathway, downregulation of early T cell activation genes, IFN-ϒ and EL-2Rα genes 15 and impairment of Jun-N-terminal kinase activity 9. The compromised immune system increases the risk of infection by pathogen like salmonella, virulence of which is increased in microgravity 16. Salmonella infection among astronauts is a well-known health hazard documented starting from Apollo and Skylab missions 16,17. Further, microgravity alters level of micro RNAs (miRNAs), many of which are related with inflammation 18 and multiple cancer types 13,18,19. However, the studies showed controversial inference based on the expression of different microRNAs. For example, expression of hsa-miR-423-5p and hsa-miR-222 in microgravity suggest the induction of breast cancer, whereas expression of hsa-miR-141 suggests the decrease in the same 19. Similar controversial miRNA expression pattern was observed for leukaemia and lung cancer 18,19. Further, as a single miRNA
Altered cytokine expression in tissues of mice subjected to simulated microgravity
Molecular and Cellular Biochemistry, 2000
Space flight is known to induce microgravity-associated immune dysfunction in humans, non-human primates and rodents. To understand the mechanism underlying these defects, several studies in rodents have been conducted in a ground-based antiorthostatic suspension (AOS) model that would mimic the effects of microgravity. In all these in vivo studies that showed the effects on cytokine profiles actually investigated the ex vivo production from culturing the cells isolated from whole organism that was exposed to space flight and/or microgravity. So, the purpose of the study was to examine the in vivo expression of cytokines in mice in immunologically important tissue environments of mice that were subjected to AOS. Cytokines such as Interleukin-1β (IL-1β), IL-2, IL-3, IL-6, Interferon-γ (IFN-γ ) and Tumor Necrosis Factor-α (TNF-α) were measured by Enzyme Linked Immunosorbent Assay (ELISA) in the homogenates of spleen tissue, lymph nodes and also in serum of AOS mice and compared with that of control mice. AOS induced no change in the IL-3 levels, but IL-1β was increased significantly whereas IL-2 levels decreased in spleen, lymph nodes and serum. IL-6 levels did not differ in spleen but were significantly increased in lymph nodes and serum of AOS mice. IFN-γ levels in spleen did not change but showed nonsignificant reduction in lymph nodes and significant reduction in serum in response to AOS. TNF-α levels in spleen and serum were unchanged and increased in lymph nodes. This in vivo cytokine study confirms the earlier findings that microgravity-simulated conditions induce tissue-specific immune response. (Mol Cell Biochem 266: [79][80][81][82][83][84][85] 2004)
SUPPRESSION OF ANTIGEN-SPECIFIC LYMPHOCYTE ACTIVATION IN MODELED MICROGRAVITY
In Vitro Cellular & Developmental Biology - Animal, 2001
Various parameters of immune suppression are observed in lymphocytes from astronauts during and after a space flight. It is difficult to ascribe this suppression to microgravity effects on immune cells in crew specimens, due to the complex physiological response to space flight and the resultant effect on in vitro immune performance. Use of isolated immune cells in true and modeled microgravity in immune performance tests, suggests a direct effect of microgravity on in vitro cellular function. Specifically, polyclonal activation of T-cells is severely suppressed in true and modeled microgravity. These recent findings suggest a potential suppression of oligoclonal antigen-specific lymphocyte activation in microgravity. We utilized rotating wall vessel (RWV) bioreactors as an analog of microgravity for cell cultures to analyze three models of antigen-specific activation. A mixed-lymphocyte reaction, as a model for a primary immune response, a tetanus toxoid response and a Borrelia burgdooCeri response, as models of a secondary immune response, were all suppressed in the RWV bioreactor. Our findings confirm that the suppression of activation observed with polyclonal models also encompasses oligoclonal antigen-specific activation.
Scientific Reports, 2014
Space flight strongly moderates human immunity but is in general well tolerated. Elucidation of the mechanisms by which zero gravity interacts with human immunity may provide clues for developing rational avenues to deal with exaggerated immune responses, e.g. as in autoimmune disease. Using two sounding rockets and one manned Soyuz launch, the influence of space flight on immunological signal transduction provoked by lipopolysaccharide (LPS) stimulation was investigated in freshly isolated peripheral blood monocytes and was compared to samples obtained from on-board centrifuge-loaded 1 g controls. The effect of microgravity on immunological signal transduction is highly specific, since LPS dependent Jun-N-terminal kinase activation is impaired in the 0 g condition, while the corresponding LPS dependent activation of p38 MAP kinase remains unaffected. Thus our results identify Jun-N-terminal kinase as a relevant target in immunity for microgravity and support using Jun-N-terminal kinase specific inhibitors for combating autoimmune disease.
Stress response and humoral immune system alterations related to chronic hypergravity in mice
Psychoneuroendocrinology, 2012
Spaceflights are known to induce stress and immune dysregulation. Centrifugation, as hindlimb unloading, is a good ground based-model to simulate altered gravity which occurs during space missions. The aim of this study was to investigate the consequences of a long-term exposure to different levels of hypergravity on the stress response and the humoral immunity in a mouse model. For this purpose, adult C57Bl/6J male mice were subjected for 21 days either to control conditions or to 2G or 3G acceleration gravity forces. Corticosterone level and anxiety behavior revealed a stress response which was associated with a decrease of body weight, after 21-day of centrifugation at 3G but not at 2G. Spleen lymphocyte lipopolysaccharide (LPS) responsiveness was diminished by 40% in the 2G group only, whereas a decrease was noted when cells were stimulated with concanavalin A for both 2G and 3G groups (about 25% and 20%, respectively) compared to controls. Pro-inflammatory chemokines (MCP-1 and IP-10) and Th1 cytokines (IFNg and IL2) were slightly decreased in the 2G group and strongly decreased in the 3G mouse group. Regarding Th2 cytokines (IL4, IL5) no further significant modification was observed, whereas the immunosuppressive cytokine IL10 was slightly increased in the 3G mice. Finally, serum IgG concentration was twice higher whereas IgA concentration was slightly increased (about 30%) and IgM were unchanged in 2G mice compared to controls. No difference was observed in the 3G group with these isotypes. Consequently, functional immune dysregulations and stress responses were dependent of the gravity level. #
Acta Astronautica, 2014
During spaceflight the immune system is one of the most affected systems of the human body. During the SIMBOX (Science in Microgravity Box) mission on Shenzhou-8, we investigated microgravity-associated long-term alterations in macrophageal cells, the most important effector cells of the immune system. We analyzed the effect of long-term microgravity on the cytoskeleton and immunologically relevant surface molecules. Human U937 cells were differentiated into a macrophageal phenotype and exposed to microgravity or 1g on a reference centrifuge on-orbit for 5 days. After on-orbit fixation, the samples were analyzed with immunocytochemical staining and confocal microscopy after landing. The unmanned Shenzhou-8 spacecraft was launched on board a Long March 2F (CZ-2F) rocket from the Jiuquan Satellite Launch Center (JSLC) and landed after a 17-day-mission. We found a severely disturbed actin cytoskeleton, disorganized tubulin