Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness
Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune syst...
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| Language: | English |
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MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/16/8546 |
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| author | Francisco J. Carrera Arias Kristina Aenlle Maria Abreu Mary A. Holschbach Lindsay T. Michalovicz Kimberly A. Kelly Nancy Klimas James P. O’Callaghan Travis J. A. Craddock |
| author_facet | Francisco J. Carrera Arias Kristina Aenlle Maria Abreu Mary A. Holschbach Lindsay T. Michalovicz Kimberly A. Kelly Nancy Klimas James P. O’Callaghan Travis J. A. Craddock |
| author_sort | Francisco J. Carrera Arias |
| collection | DOAJ |
| description | Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic–pituitary–adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood–brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic–pituitary–gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA–HPG–Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal–glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI. |
| first_indexed | 2024-03-10T08:46:16Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:46:16Z |
| publishDate | 2021-08-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d1d7bc20743f4b7ab3e55be8ceb28ef02023-11-22T07:56:47ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216854610.3390/ijms22168546Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War IllnessFrancisco J. Carrera Arias0Kristina Aenlle1Maria Abreu2Mary A. Holschbach3Lindsay T. Michalovicz4Kimberly A. Kelly5Nancy Klimas6James P. O’Callaghan7Travis J. A. Craddock8Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USAInstitute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USAInstitute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USADepartment of Psychology & Neuroscience, College of Psychology, Nova Southeastern University, Fort Lauderdale, FL 33314, USAHealth Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USAHealth Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USAInstitute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USAHealth Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USAInstitute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USAGulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic–pituitary–adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood–brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic–pituitary–gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA–HPG–Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal–glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI.https://www.mdpi.com/1422-0067/22/16/8546neuroinflammationblood–brain barrierlogical modelingregulatory biologyhomeostatic regulationtreatment course prediction |
| spellingShingle | Francisco J. Carrera Arias Kristina Aenlle Maria Abreu Mary A. Holschbach Lindsay T. Michalovicz Kimberly A. Kelly Nancy Klimas James P. O’Callaghan Travis J. A. Craddock Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness International Journal of Molecular Sciences neuroinflammation blood–brain barrier logical modeling regulatory biology homeostatic regulation treatment course prediction |
| title | Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness |
| title_full | Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness |
| title_fullStr | Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness |
| title_full_unstemmed | Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness |
| title_short | Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness |
| title_sort | modeling neuroimmune interactions in human subjects and animal models to predict subtype specific multidrug treatments for gulf war illness |
| topic | neuroinflammation blood–brain barrier logical modeling regulatory biology homeostatic regulation treatment course prediction |
| url | https://www.mdpi.com/1422-0067/22/16/8546 |
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