A Logic Model of Neuronal-Glial Interaction Suggests Altered Homeostatic Regulation in the Perpetuation of Neuroinflammation

Abstract

Aberrant inflammatory signaling between neuronal and glial cells can develop into a persistent sickness behavior-related disorders, negatively impacting learning, memory, and neurogenesis. While there is an abundance of literature describing these interactions, there still lacks a comprehensive mathematical model describing the complex feed-forward and feedback mechanisms of neural-glial interaction. Here we compile molecular and cellular signaling information from various studies and reviews in the literature to create a logically-consistent, theoretical model of neural-glial interaction in the brain to explore the role of neuron-glia homeostatic regulation in the perpetuation of neuroinflammation. Logic rules are applied to this connectivity diagram to predict the system's homeostatic behavior. We validate our model predicted homeostatic profiles against RNAseq gene expression profiles in a mouse model of stress primed neuroinflammation. A meta-analysis was used to calculate the significance of similarity between the inflammatory profiles of mice exposed to diisopropyl fluorophostphate (DFP) [with and without prior priming by the glucocorticoid stress hormone corticosterone (CORT)], with the equilibrium states predicted by the model, and to provide estimates of the degree of the neuroinflammatory response. Beyond normal homeostatic regulation, our model predicts an alternate self-perpetuating condition consistent with chronic neuroinflammation. RNAseq gene expression profiles from the cortex of mice exposed to DFP and CORT+DFP align with this predicted state of neuroinflammation, whereas the alignment to CORT alone was negligible. Simulations of putative treatment strategies post-exposure were shown to be theoretically capable of returning the system to a state of typically healthy regulation with broad-acting anti-inflammatory agents showing the highest probability of success. The results support a role for the brain's own homeostatic drive in perpetuating the chronic neuroinflammation associated with exposure to the organophosphate DFP, with and without CORT priming. The deviation of illness profiles from exact model predictions suggests the presence of additional factors or of lasting changes to the brain's regulatory circuitry specific to each exposure.

DRUGPATH: The Drug Gene Pathway Meta-Database

“…DRUGPATH predicted that these two drugs would interact via immune pathways, such as the aptly named "immune pathway" affected by almost all genes connected to enbrel and the ELANE gene from mifepristone. This interaction suggests that these drugs in combination would likely affect immune functioning, which aligns to the proposed treatment strategy from our group of enbrel and mifepristone for GWI [5,7,10]. This is consistent with the expected effect of these drugs, and would normally be monitored when undertaking these drug treatment courses.…”

“…Here, the major hypothesis of GWI pathophysiology involves the combination of stress and exposure to battlefield neurotoxins triggering a neuroinflammatory cascade, leading to altered homeostatic regulation [5][6][7]. Our computational models have predicted the inhibition of Th1 inflammatory cytokines (e.g., TNFα) followed by inhibition of the GCR would return the patient back to stable homeostatic regulation [7,10]. Such models indicated the use of enbrel and mifepristone.…”

“…GWI is a chronic multi-symptom illness characterized by gastrointestinal, muscle, and cognitive dysfunction stemming from exposure to battlefield neurotoxins during the 1990-91 Persian Gulf War [5][6][7]. Prior analysis of gene expression in peripheral blood mononuclear cells [8] as well as the dynamic regulatory modeling of the neuro-endocrine-immune response to an exercise challenge [7,9] predicted that an initial inhibition of Th1 cytokines, followed by glucocorticoid receptor (GCR) inhibition, would bring patients from the chronic homeostatic regulation induced by neurotoxin exposure back to a more healthy, stable homeostatic regulatory state [7,9,10]. While subsequent analysis [5] suggested that the best treatment course may be accomplished using enbrel, a tumor necrosis factor alpha (TNFα) inhibitor [11], in combination with the antiglucocorticoid mifepristone [12], great precaution must be used due to the novelty of this treatment regimen as well as the chemical sensitivity found in patients with GWI.…”

Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans

“…Deployed soldiers were exposed to significant physiological stressors such as exercise and extreme temperatures ( Young et al, 1992 ; Sapolsky, 1998 ; Sullivan et al, 2003 ) that had the potential to interact with or modulate the responses to chemical exposures. As such, several studies investigating the contribution of nerve agent exposure to GWI have found positive correlations to illness symptomology when sarin surrogates have been combined with a stressor ( O’Callaghan et al, 2015 ; Locker et al, 2017 ; Ashbrook et al, 2018 ; Koo et al, 2018 ; Miller et al, 2018 ; Craddock et al, 2018 ; Michalovicz et al, 2019 ; Belgrad et al, 2019 ). In this GWI rodent model, a single dose of DFP is preceded by a chronic (4–7 day) exposure to exogenous corticosterone (CORT) provided in the drinking water (200 mg/L) to mimic the high physiological stress experienced by soldiers during deployment.…”

“…Though currently acute in scope, the extensive evaluation of this model has strongly supported the role of neuroimmune dysfunction as the underlying cause of GWI showing that this combination of exposures results in CORT priming of the DFP neuroinflammatory response leading to significantly increased inflammatory cytokine mRNA throughout the brain, including cortex, hippocampus, and striatum ( O’Callaghan et al, 2015 ; Locker et al, 2017 ; Koo et al, 2018 ; Miller et al, 2018 ), along with alterations in neuroimmune signaling via histone modification and DNA methylation changes ( Ashbrook et al, 2018 ) shortly after the exposures. Furthermore, evaluation of this paradigm using a literature-derived, logic model of neuron-glia interactions indicated the potential for GWI to derive from an aberrant homeostatic neuroinflammatory profile ( Craddock et al, 2018 ). Notably, these neuroinflammatory effects occur in the absence of significant peripheral inflammation ( Michalovicz et al, 2019 ).…”