Modeling cytokine regulatory network dynamics driving neuroinflammation in central nervous system disorders

Abstract

A central goal of pharmacological efforts to treat central nervous system (CNS) diseases is to develop systemic therapeutics that can restore CNS homeostasis. Achieving this goal requires a fundamental understanding of CNS function within the organismal context so as to leverage the mechanistic insights on the molecular basis of cellular and tissue functions towards novel drug target identification. The immune system constitutes a key link between the periphery and CNS, and many neurological disorders and neurodegenerative diseases are characterized by immune dysfunction. We review the salient opportunities for applying computational models to CNS disease research, and summarize relevant approaches from studies of immune function and neuroinflammation. While the accurate prediction of disease-related phenomena is often considered the central goal of modeling studies, we highlight the utility of computational modeling applications beyond making predictions, particularly for drawing counterintuitive insights from model-based analysis of multi-parametric and time series data sets.

Novel Influences of IL-10 on CNS Inflammation Revealed by Integrated Analyses of Cytokine Networks and Microglial Morphology

“…Even if astrocyte-mediated feedback regulation of microglial inflammation were not exclusively controlled by TGFβ, our model illustrates a plausible mechanism from the perspective of the observed process dynamics. Furthermore, we have argued that computational modeling can be utilized for numerous purposes other than accurately recapitulating or predicting the precise mechanisms of function (Anderson and Vadigepalli, in press ). Alternatively, as in our study, modeling can be used to show that negative feedback processes—regardless of their precise molecular mechanisms—are sufficient to explain the effect of IL-10 occlusion on the adaptive response to CNS insult.…”

Using NEURON for Reaction-Diffusion Modeling of Extracellular Dynamics

“…All of these processes are currently the subject of multiscale modeling at varying degrees of sophistication (Anderson and Vadigepalli, 2016 ; Linninger et al, 2016 ; Calvetti et al, 2018 ; Durka et al, 2018 ; Zhao et al, 2018 ). Although it would not be practical to incorporate these many types of simulation within NEURON, there will be possibilities for cross-simulator communication providing complex multiphysics simulations in the future (Djurfeldt et al, 2010 ).…”

How Repair-or-Dispose Decisions Under Stress Can Initiate Disease Progression

“…In the last couple of decades, several modeling approaches have been put forward to better understand processes underlying neurodegeneration and neural tissue resilience ( Kolodkin et al., 2012 ; Anderson and Vadigepalli, 2016 ; Lloret-Villas et al., 2017 ). The modeling approaches vary widely and address aspects ranging from nervous system energy metabolism ( Cloutier et al., 2009 ; Lewis et al., 2010 ), protein degradation ( Cloutier and Wellstead, 2012 ; Ouzounoglou et al., 2014 ), and blood-brain barrier transport ( Garg and Verma, 2006 ; Martins et al., 2012 ) to tauopathy ( Proctor and Gray, 2010 ; Yuraszeck et al, 2010 ).…”