Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness

Abstract

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.

Military exposures and Gulf War illness in veterans with and without posttraumatic stress disorder

“…Observations that veterans with GWI show higher levels of markers of inflammation have fueled speculation that GWI is a neuroimmune condition (Carrera Arias et al., 2021; James et al., 2019). Conditions or exposures that enhance inflammation might be etiological contributors to GWI.…”

A Projectile Concussive Impact Model Produces Neuroinflammation in Both Mild and Moderate-Severe Traumatic Brain Injury

“…The situation where the logic indicates that the current state prefers to evolve toward itself indicates that the current state is a stable state of the system (i.e., it does not evolve in time). The qPCR gene expression neuroimmune profiles from the TBI rat model were then compared to each model-predicted steady-state behavior of the neuroimmune system through the application of Brown’s theoretical approximation [ 39 ] of Fisher’s statistics, as conducted in our previous work [ 33 , 38 , 40 , 41 , 42 , 43 ]. This method was chosen as it provides a meta-analysis technique to combine non-independent probabilities and obtain an overall significance measure P based on a set of p -values obtained from independent t -tests.…”

Intermittent systemic exposure to lipopolysaccharide-induced inflammation disrupts hippocampal long-term potentiation and impairs cognition in aging male mice

“…Under terminal isoflurane inhalation-induced anesthesia, animals were euthanized via cardiocentesis followed by rapid decapitation. As we have done previously 45, 46 , total RNA was isolated from discrete brain regions (frontal cortex and hippocampus) and cytokine expression measured by qRT-PCR analysis as previously described. Briefly, total RNA was isolated from the brain tissue using Trizol Reagent (Thermo Fisher Scientific, Waltham, MA, USA), Phase-lock heavy gel (Eppendorf AG, Hamburg, Germany), and RNeasy mini spin columns (Qiagen, Valencia, CA, USA) according to the manufacturer’s instructions.…”