Dysregulated neural immune activity contributes to the pathogenesis of diverse diseases, including Alzheimer’s disease, traumatic brain injury, and lysosomal storage disorders, among others. Understanding neural immune function and identification of strategies to restore healthy or homeostatic immune activity holds the potential to transform our ability to treat neurodegenerative diseases. Neural immune activity is a complex system, consisting of intracellular regulation of diverse immune genes by phospho-signaling cascades that ultimately control glial phenotypes and expression of extra-cellular signaling factors, such as cytokines, that communicate between cells and exacerbate dysfunction. This talk will consist of two parts. In the first part, I will discuss our multivariate systems analysis of neuroinflammatory astrocyte signaling in the lysosomal storage disorder, mucolipidosis IV. By integrating systems level phospho-signaling, cytokine expression, and RNAseq data, we identified a central neuroinflammatory signaling pathway regulated by sphingosine-1-phospate (S1P) that promotes astrocyte activation in this disease. Based on our systems analysis, we identified the S1P inhibitor fingolimod (FTY720) as a translationally relevant pharmacologic approach to restore homeostatic levels of phospho-signaling and cytokine expression and promote normal lysosomal morphology in astrocytes.
In the second part of my talk, I will discuss our work to identify neuroinflammatory signaling responsible for cognitive deficit after repetitive mild traumatic brain injury (mTBI). We use a weight drop closed head injury mouse model relevant to sports injury in which a subset of mice experience cognitive deficit despite having no overt signs of neuronal injury. Using a non-invasive optical cerebral blood flow sensor, we found that mice with acutely low cerebral blood flow after mTBI would suffer long term memory deficit and had elevated acute microglial activation. Surprisingly, microglial activation was accompanied by neuronal pro-inflammatory phospho-signaling and cytokine expression, suggesting for the first time that neural immunity and cognitive deficit depends on the interplay between glia and neurons. Moreover, our ongoing studies suggest that inhibition of phospho-signaling using translationally relevant small molecules has the potential to restore cognitive function after repetitive mTBI.