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      Beyond Low-Earth Orbit: Characterizing Immune and microRNA Differentials following Simulated Deep Spaceflight Conditions in Mice

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          Summary

          Spaceflight missions can cause immune system dysfunction in astronauts with little understanding of immune outcomes in deep space. This study assessed immune responses in mice following ground-based, simulated deep spaceflight conditions, compared with data from astronauts on International Space Station missions. For ground studies, we simulated microgravity using the hindlimb unloaded mouse model alone or in combination with acute simulated galactic cosmic rays or solar particle events irradiation. Immune profiling results revealed unique immune diversity following each experimental condition, suggesting each stressor results in distinct circulating immune responses, with clear consequences for deep spaceflight. Circulating plasma microRNA sequence analysis revealed involvement in immune system dysregulation. Furthermore, a large astronaut cohort showed elevated inflammation during low-Earth orbit missions, thereby supporting our simulated ground experiments in mice. Herein, circulating immune biomarkers are defined by distinct deep space irradiation types coupled to simulated microgravity and could be targets for future space health initiatives.

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          Highlights

          • •

            Murine immune profiles from simulated deep spaceflight conditions were analyzed

          • •

            Immune profiling revealed unique immune diversity with each experimental condition

          • •

            Plasma microRNA sequence analysis revealed involvement in immune system dysregulation

          • •

            Astronaut data showed elevated inflammation during low-Earth orbit missions

          Abstract

          Immunology; Space Sciences

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          Most cited references95

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          The Molecular Signatures Database (MSigDB) hallmark gene set collection.

          Arthur Liberzon, Chet Birger, Helga Thorvaldsdóttir … (2015)
          The Molecular Signatures Database (MSigDB) is one of the most widely used and comprehensive databases of gene sets for performing gene set enrichment analysis. Since its creation, MSigDB has grown beyond its roots in metabolic disease and cancer to include >10,000 gene sets. These better represent a wider range of biological processes and diseases, but the utility of the database is reduced by increased redundancy across, and heterogeneity within, gene sets. To address this challenge, here we use a combination of automated approaches and expert curation to develop a collection of "hallmark" gene sets as part of MSigDB. Each hallmark in this collection consists of a "refined" gene set, derived from multiple "founder" sets, that conveys a specific biological state or process and displays coherent expression. The hallmarks effectively summarize most of the relevant information of the original founder sets and, by reducing both variation and redundancy, provide more refined and concise inputs for gene set enrichment analysis.
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            Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation

            Jacob O'Brien, Heyam Hayder, Yara Zayed … (2018)
            MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression. The majority of miRNAs are transcribed from DNA sequences into primary miRNAs and processed into precursor miRNAs, and finally mature miRNAs. In most cases, miRNAs interact with the 3′ untranslated region (3′ UTR) of target mRNAs to induce mRNA degradation and translational repression. However, interaction of miRNAs with other regions, including the 5′ UTR, coding sequence, and gene promoters, have also been reported. Under certain conditions, miRNAs can also activate translation or regulate transcription. The interaction of miRNAs with their target genes is dynamic and dependent on many factors, such as subcellular location of miRNAs, the abundancy of miRNAs and target mRNAs, and the affinity of miRNA-mRNA interactions. miRNAs can be secreted into extracellular fluids and transported to target cells via vesicles, such as exosomes, or by binding to proteins, including Argonautes. Extracellular miRNAs function as chemical messengers to mediate cell-cell communication. In this review, we provide an update on canonical and non-canonical miRNA biogenesis pathways and various mechanisms underlying miRNA-mediated gene regulations. We also summarize the current knowledge of the dynamics of miRNA action and of the secretion, transfer, and uptake of extracellular miRNAs.
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              IL-6 in inflammation, immunity, and disease.

              Toshio Tanaka, Masashi Narazaki, Tadamitsu Kishimoto (2014)
              Interleukin 6 (IL-6), promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis, and immune reactions. Although its expression is strictly controlled by transcriptional and posttranscriptional mechanisms, dysregulated continual synthesis of IL-6 plays a pathological effect on chronic inflammation and autoimmunity. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody was developed. Various clinical trials have since shown the exceptional efficacy of tocilizumab, which resulted in its approval for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Moreover, tocilizumab is expected to be effective for other intractable immune-mediated diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated to facilitate the development of more specific therapeutic approaches and analysis of the pathogenesis of specific diseases.
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                Author and article information

                Contributors
                Afshin Beheshti
                Journal
                Journal ID (nlm-ta): iScience
                Journal ID (iso-abbrev): iScience
                Title: iScience
                Publisher: Elsevier
                ISSN (Electronic): 2589-0042
                Publication date PMC-release: 25 November 2020
                Publication date Collection: 18 December 2020
                Publication date (Electronic): 25 November 2020
                Volume: 23
                Issue: 12
                Electronic Location Identifier: 101747
                Affiliations
                [1 ]Universities Space Research Association, Columbia, MD 21046, USA
                [2 ]Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94043, USA
                [3 ]Department of Biomedical Engineering, Center for Biotechnology & Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
                [4 ]Department of Biological Sciences, San Jose State University, San Jose, CA 95112, USA
                [5 ]Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX 77555, USA
                [6 ]NASA Johnson Space Center, Houston, TX 77058, USA
                [7 ]Department of Neurobiology/Pharmacology, Morehouse School of Medicine, Atlanta, GA 30310, USA
                [8 ]Center for Radiological Research, Columbia University, New York, NY 10027, USA
                [9 ]KBR, Space Biosciences Division, NASA Ames Research Center, Moffett Field, CA 94043, USA
                Author notes
                [∗ ]Corresponding author afshin.beheshti@ 123456nasa.gov
                [10]

                Lead Contact

                Article
                Publisher Item ID: S2589-0042(20)30944-5 Publisher ID: 101747
                DOI: 10.1016/j.isci.2020.101747
                PMC ID: 7756144
                PubMed ID: 33376970
                SO-VID: 891d28dd-f9ba-46c1-bf87-a1d5d3e29661
                Copyright © © 2020 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 15 June 2020
                Date revision received : 16 October 2020
                Date accepted : 26 October 2020
                Categories
                Subject: Article

                Keywords: immunology,space sciences
                Data availability:
                Keywords: immunology, space sciences

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