Abstract
BackgroundUnderstanding the interdependencies among inflammatory mediators of tissue damage following traumatic brain injury (TBI) is essential in providing effective, patient-specific care. Activated microglia and elevated concentrations of inflammatory signaling molecules reflect the complex cascades associated with acute neuroinflammation and are predictive of recovery after TBI. However, clinical TBI studies to date have not focused on modeling the dynamic temporal patterns of simultaneously evolving inflammatory mediators, which has potential in guiding the design of future immunomodulation intervention studies.MethodsWe derived a mathematical model consisting of ordinary differential equations (ODE) to represent interactions between pro- and anti-inflammatory cytokines, M1- and M2-like microglia, and central nervous system (CNS) tissue damage. We incorporated variables for several cytokines, interleukin (IL)-1β, IL-4, IL-10, and IL-12, known to have roles in microglial activation and phenotype differentiation. The model was fit to cerebrospinal fluid (CSF) cytokine data, collected during the first 5 days post-injury in n = 89 adults with severe TBI. Ensembles of model fits were produced for three patient subgroups: (1) a favorable outcome group (GOS = 4,5) and (2) an unfavorable outcome group (GOS = 1,2,3) both with lower pro-inflammatory load, and (3) an unfavorable outcome group (GOS = 1,2,3) with higher pro-inflammatory load. Differences in parameter distributions between subgroups were ranked using Bhattacharyya metrics to identify mechanistic differences underlying the neuroinflammatory patterns of patient groups with different TBI outcomes.ResultsOptimal model fits to data showed different microglial and damage responses by patient subgroup. Upon comparison of model parameter distributions, unfavorable outcome groups were characterized by either a prolonged, pathophysiological or a transient, sub-physiological course of neuroinflammation.ConclusionBy developing a mathematical characterization of inflammatory processes informed by clinical data, we have created a system for exploring links between acute neuroinflammatory components and patient outcome in severe TBI.
Highlights
Understanding the interdependencies among inflammatory mediators of tissue damage following traumatic brain injury (TBI) is essential in providing effective, patient-specific care
Microglial activation from resting state Since the contemporary concept of resting microglial activation to a classic pro-inflammatory M1-like microglia (M1)-like or an alternative anti-inflammatory M2-like microglia (M2)-like state is still evolving, our model focuses on influences from the central nervous system (CNS) cytokine microenvironment that likely affect microglial dynamics following TBI
Grouping by 6-month Glasgow Outcome Scale (GOS) score was not implemented in cluster 1 due to the small number of favorable outcome patients belonging to this group (n = 2)
Summary
Understanding the interdependencies among inflammatory mediators of tissue damage following traumatic brain injury (TBI) is essential in providing effective, patient-specific care. Each phenotypic state has its respective role in the neuroinflammatory sequence including phagocytosis of damaged and dysfunctional neurons, neurogenesis, tissue repair and restoration, and immune regulation [2, 5, 10]. Distinguishing these functional phenotypes in humans by in vivo imaging techniques (such as positron emission tomography) is still in its infancy [11]. Alternative methodologies are warranted to complement these technological advancements and to characterize the temporal progression of microglial activation and functionality post-injury
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