Spaceflight-Associated Immune System Modifications

Spaceflight is an adverse environment characterized by a unique combination of stressors affecting almost all physiological systems, including the immune system. Indeed, several studies have shown that about 50% of the astronauts have faced immunological troubles. Here, we will review how spaceflight affects immune cell development, innate as well as adaptive immunity, required to ensure an efficient protection of the host, with a particular focus on T and B cells. Indeed, to better appreciate the risks associated to future long-duration space missions and to develop pharmacologic or nutritional countermeasures allowing immune system protection, it is mandatory to fully understand how these cell types are affected by space conditions. Finally, we will compare immune changes observed in astronauts with those encountered in the elderly, thereby illustrating the societal interest of space research

Large area SiC-UV phothodiode for spectroscopy portable system

In this work, we present the extensive characterization of large area Silicon Carbide based UV sensors candidate for outdoors spectroscopic applications of gas or liquid. The proposed SiC Schottky devices exhibit dark current density of 0.12 nA/cm2 @ 15 V, a 0.12 A/W responsivity @ 300 nm, optimal visible blindness and switching time of ~ 190 ns. Effects of temperature on the sensor performance, of crucial interest for outdoors applications, are also examined in the range from -20 °C to 90 °C.Published2931 - 29367TM. Sviluppo e Trasferimento TecnologicoJCR Journa

Sicilia—silicon carbide detectors for intense luminosity investigations and applications

Silicon carbide (SiC) is a compound semiconductor, which is considered as a possible alternative to silicon for particles and photons detection. Its characteristics make it very promising for the next generation of nuclear and particle physics experiments at high beam luminosity. Silicon Carbide detectors for Intense Luminosity Investigations and Applications (SiCILIA) is a project starting as a collaboration between the Italian National Institute of Nuclear Physics (INFN) and IMM-CNR, aiming at the realization of innovative detection systems based on SiC. In this paper, we discuss the main features of silicon carbide as a material and its potential application in the field of particles and photons detectors, the project structure and the strategies used for the prototype realization, and the first results concerning prototype production and their performance

Effects of gravity changes encountered during spaceflight on dendritic cells and T lymphopoiesis

Avec l’effervescence de la conquête spatiale, le nombre et la durée des missions spatiales s’amplifient. Aujourd’hui, nous savons que les conditions extrêmes rencontrées dans l’espace ont un effet délétère sur l’organisme. Les changements de gravité constituent des stress qui impactent de nombreuses fonctions physiologiques comme le système immunitaire. Cependant, les effets de ces changements et les mécanismes moléculaires par lesquels ils affectent l’immunité sont encore peu connus. Dans ce contexte, nous avons étudié l’impact des modifications gravitaires sur les cellules dendritiques (DC) et les lymphocytes T (LT) murins.En effet, bien que les DC soient essentielles à la réponse immunitaire, très peu d’études se sont intéressées à comprendre les effets des stress gravitaires sur ces cellules. Dans une première partie, nous avons montré que les DC exposées à un stress microgravitaire présentent un défaut de phénotype de maturation associé à une diminution de leur fonction de polarisation des LT CD4+ vers un profil Th1. L’étude des mécanismes impliqués dans ces altérations a permis de mettre en évidence un défaut d’activation de la voie de NFkB ainsi que des modulations des mécanismes épigénétiques liés au couple EZH2/JMJD3 et à la triméthylation de la lysine 27 de l’histone H3 (H3K27me3). Notre étude a notamment montré que le niveau d’H3K27me3 est dérégulé par la microgravité et que l’expression d’EZH2 et de JMJD3 est aussi impactée. Dans une seconde partie, nous avons démontré qu’EZH2 et H3K27me3 sont importants dans la régulation du développement des LT. En effet, le thymus de souris exposées à l’hypergravité présente une modification du répertoire TCRb qui peut s’expliquer par des modifications d’H3K27me3 au niveau du locus TCRb et par l’implication d’EZH2 dans la régulation de la structure de la chromatine de ce locus.Une meilleure compréhension des mécanismes menant à l’altération du système immunitaire par le stress gravitaire est importante, pour, à terme, permettre de développer des stratégies visant à limiter ses effets sur le système immunitaire lors des futurs voyages spatiaux.With the effervescence of the space conquest, the number and the duration of space missions are increasing. Today, we know that extreme conditions encountered in space have a deleterious effect on the organism. Gravity changes constitute stresses that impact physiological functions and especially the immune system. However, effects of gravity changes on immunity and molecular mechanisms by which they affect it are still poorly understood. In this context, we studied the impact of gravity changes on murine dendritic cells (DC) and T lymphocytes (LT).Despite the fact that DC are essential for the immune response, very few data about the impact of gravitational stresses on these cells exist. In this context, the first part of this thesis showed that microgravity impairs DC maturation phenotype and their function to drive Th1 polarization. These alterations seem to be linked to a NFkB activation defect but could also be explained by epigenetic mechanism through the deregulation of EZH2/JMJD3 and H3K27me3. Our study showed that H3K27me3 is deregulated by microgravity and that EZH2 and JMJD3 are also impacted. In a second part, we showed that EZH2 and H3K27me3 are important for the regulation of LT development. Indeed, we showed that the thymus of hypergravity exposed mice presents modifications of the TCRb repertoire that is linked to H3K27me3 changes at the TCRb locus, and to the regulation of the chromatin structure of this locus by EZH2.A better understanding of the mechanisms by which microgravity impairs the immune system will allow to develop strategies to limit its outcome during future spaceflights

Effets des modifications gravitaires rencontrées lors des vols spatiaux sur les cellules dendritiques et la lymphopoïèse T

With the effervescence of the space conquest, the number and the duration of space missions are increasing. Today, we know that extreme conditions encountered in space have a deleterious effect on the organism. Gravity changes constitute stresses that impact physiological functions and especially the immune system. However, effects of gravity changes on immunity and molecular mechanisms by which they affect it are still poorly understood. In this context, we studied the impact of gravity changes on murine dendritic cells (DC) and T lymphocytes (LT).Despite the fact that DC are essential for the immune response, very few data about the impact of gravitational stresses on these cells exist. In this context, the first part of this thesis showed that microgravity impairs DC maturation phenotype and their function to drive Th1 polarization. These alterations seem to be linked to a NFkB activation defect but could also be explained by epigenetic mechanism through the deregulation of EZH2/JMJD3 and H3K27me3. Our study showed that H3K27me3 is deregulated by microgravity and that EZH2 and JMJD3 are also impacted. In a second part, we showed that EZH2 and H3K27me3 are important for the regulation of LT development. Indeed, we showed that the thymus of hypergravity exposed mice presents modifications of the TCRb repertoire that is linked to H3K27me3 changes at the TCRb locus, and to the regulation of the chromatin structure of this locus by EZH2.A better understanding of the mechanisms by which microgravity impairs the immune system will allow to develop strategies to limit its outcome during future spaceflights.Avec l’effervescence de la conquête spatiale, le nombre et la durée des missions spatiales s’amplifient. Aujourd’hui, nous savons que les conditions extrêmes rencontrées dans l’espace ont un effet délétère sur l’organisme. Les changements de gravité constituent des stress qui impactent de nombreuses fonctions physiologiques comme le système immunitaire. Cependant, les effets de ces changements et les mécanismes moléculaires par lesquels ils affectent l’immunité sont encore peu connus. Dans ce contexte, nous avons étudié l’impact des modifications gravitaires sur les cellules dendritiques (DC) et les lymphocytes T (LT) murins.En effet, bien que les DC soient essentielles à la réponse immunitaire, très peu d’études se sont intéressées à comprendre les effets des stress gravitaires sur ces cellules. Dans une première partie, nous avons montré que les DC exposées à un stress microgravitaire présentent un défaut de phénotype de maturation associé à une diminution de leur fonction de polarisation des LT CD4+ vers un profil Th1. L’étude des mécanismes impliqués dans ces altérations a permis de mettre en évidence un défaut d’activation de la voie de NFkB ainsi que des modulations des mécanismes épigénétiques liés au couple EZH2/JMJD3 et à la triméthylation de la lysine 27 de l’histone H3 (H3K27me3). Notre étude a notamment montré que le niveau d’H3K27me3 est dérégulé par la microgravité et que l’expression d’EZH2 et de JMJD3 est aussi impactée. Dans une seconde partie, nous avons démontré qu’EZH2 et H3K27me3 sont importants dans la régulation du développement des LT. En effet, le thymus de souris exposées à l’hypergravité présente une modification du répertoire TCRb qui peut s’expliquer par des modifications d’H3K27me3 au niveau du locus TCRb et par l’implication d’EZH2 dans la régulation de la structure de la chromatine de ce locus.Une meilleure compréhension des mécanismes menant à l’altération du système immunitaire par le stress gravitaire est importante, pour, à terme, permettre de développer des stratégies visant à limiter ses effets sur le système immunitaire lors des futurs voyages spatiaux

Simulated Microgravity Disrupts Nuclear Factor κB Signaling and Impairs Murine Dendritic Cell Phenotype and Function

During spaceflights, astronauts face different forms of stress (e.g., socio-environmental and gravity stresses) that impact physiological functions and particularly the immune system. In this context, little is known about the effect of such stress on dendritic cells (DCs). First, we showed that hypergravity, but not chronic ultra-mild stress, a socio-environmental stress, induced a less mature phenotype characterized by a decreased expression of MHCII and co-stimulatory molecules. Next, using the random positioning machine (RPM), we studied the direct effects of simulated microgravity on either splenic DCs or Flt-3L-differentiated bone marrow dendritic cells (BMDCs). Simulated microgravity was found to reduce the BM-conventional DC (cDC) and splenic cDC activation/maturation phenotype. Consistent with this, BMDCs displayed a decreased production of pro-inflammatory cytokines when exposed to microgravity compared to the normogravity condition. The induction of a more immature phenotype in microgravity than in control DCs correlated with an alteration of the NFκB signaling pathway. Since the DC phenotype is closely linked to their function, we studied the effects of microgravity on DCs and found that microgravity impaired their ability to induce naïve CD4 T cell survival, proliferation, and polarization. Thus, a deregulation of DC function is likely to induce immune deregulation, which could explain the reduced efficiency of astronauts’ immune response

Chronic Hypergravity Induces a Modification of Histone H3 Lysine 27 Trimethylation at TCRβ Locus in Murine Thymocytes

Gravity changes are major stressors encountered during spaceflight that affect the immune system. We previously evidenced that hypergravity exposure during gestation affects the TCRβ repertoire of newborn pups. To identify the mechanisms underlying this observation, we studied post-translational histone modifications. We first showed that among the four studied post-translational histone H3 modifications, only lysine 27 trimethylation (H3K27me3) is downregulated in the thymus of mice exposed to 2× g for 21 days. We then asked whether the TCRβ locus chromatin structure is altered by hypergravity exposure. ChIP studies performed on four Vβ segments of the murine double-negative SCIET27 thymic cell line, which corresponds to the last maturation stage before V(D)J recombination, revealed increases in H3K27me3 after 2× g exposure. Finally, we evaluated the implication for the EZH2 methyltransferase in the regulation of the H3K27me3 level at these Vβ segments by treating SCIET27 cells with the GSK126-specific inhibitor. These experiments showed that the downregulation of H3K27me3 contributes to the regulation of the Vβ germline transcript expression that precedes V(D)J recombination. These data show that modifications of H3K27me3 at the TCRβ locus likely contribute to an explanation of why the TCR repertoire is affected by gravity changes and imply, for the first time, EZH2 in the regulation of the TCRβ locus chromatin structure

Heart lipid accumulation in obese non-diabetic rats: Effect of weight loss.

BACKGROUND AND AIM: The aim of this study was to investigate lipid content and expression of genes involved in lipid metabolism, in lean and obese non-diabetic rats and in obese rats undergoing food restriction and weight loss. METHODS AND RESULTS: We studied lean and genetically obese Zucker rats (fa/fa). Another group of obese rats were food restricted to lose 20% of initial body weight. We measured expression of genes involved in lipid oxidation and synthesis. Tissue triglyceride content, cell apoptosis and tissue fibrosis were also evaluated. The hearts of obese rats have higher triglyceride content compared to lean controls despite an increased expression of genes involved in fatty acid oxidation (PPAR alpha, PGC-1 alpha, CPT-I, ACO, UCP3). No differences were found in apoptosis and tissue fibrosis between the two phenotypes. Weight loss resulted in a significant reduction in heart lipid content, while the expression of genes involved in fatty acid oxidation remained elevated. CONCLUSION: In contrast to data reported in diabetic rats, pathways of lipid oxidation are increased rather than decreased in insulin-resistant obese rats. Food restriction reduced heart triglyceride content while lipid-oxidizing genes remained elevated, probably as a consequence of lipid oversupply coming from the endogenous source

Heart lipid accumulation in obese non-diabetic rats: Effect of weight loss

BACKGROUND AND AIM: The aim of this study was to investigate lipid content and expression of genes involved in lipid metabolism, in lean and obese non-diabetic rats and in obese rats undergoing food restriction and weight loss. METHODS AND RESULTS: We studied lean and genetically obese Zucker rats (fa/fa). Another group of obese rats were food restricted to lose 20% of initial body weight. We measured expression of genes involved in lipid oxidation and synthesis. Tissue triglyceride content, cell apoptosis and tissue fibrosis were also evaluated. The hearts of obese rats have higher triglyceride content compared to lean controls despite an increased expression of genes involved in fatty acid oxidation (PPAR alpha, PGC-1 alpha, CPT-I, ACO, UCP3). No differences were found in apoptosis and tissue fibrosis between the two phenotypes. Weight loss resulted in a significant reduction in heart lipid content, while the expression of genes involved in fatty acid oxidation remained elevated. CONCLUSION: In contrast to data reported in diabetic rats, pathways of lipid oxidation are increased rather than decreased in insulin-resistant obese rats. Food restriction reduced heart triglyceride content while lipid-oxidizing genes remained elevated, probably as a consequence of lipid oversupply coming from the endogenous source