Targeting the Epigenetic Factors of Neuroinflammation

Abstract

Currently, there are no effective treatments for traumatic brain injury (TBI). This is because the mechanisms behind post-injury neuroinflammation are not well understood. This project studies a novel signaling pathway responsible for the activation of microglia post-TBI. Its goal is to identify epigenetic factors of neuroinflammation that may be targeted with future therapies.

We are examining the possibility that class IIa Histone Deacetylases (HDACs), particularly HDAC7, are responsible for initiating the inflammatory response after TBI. In addition, we plan to explore what its upstream regulation factors may be. One possible upstream regulation factor explored is regulating Kinase 2, also known as Par1b (Par1b/MARK2), since prior research indicates that a deficiency in Par1b/MARK2 increased the inflammatory response of microglia in a mouse model of TBI. In our experiments, we examined brains from sham mice (i.e., without head injury) and mice subjected to closed head injury (CHI). Our experiments made use of wild-type mice and mice deficient in Par1b/MARK2. Qualitative analyses were conducted using fluorescent microscopy imaging of immunohistochemistry. Using cell-specific markers of inflammation, we found an increase in astrocytic marker GFAP (glial fibrillary acidic protein) and microglial protein IBA1 (ionized calcium binding protein) expression in the cortex of the mice after CHI. These increases were dramatic ipsilaterally (same side) to the injury, but only moderate contralaterally (opposite side). In the control brains (sham operates), little to no increase in these markers were detected.

In our experiments, we observed increased expression of HDAC7 in post-TBI microglia as well as in reactive GFAP-expressing astrocytes. Others have observed that Par1b/MARK2 may negatively regulate HDAC7 activity and there is evidence that HDAC7 is an inhibitor of anti-inflammatory genes.