Int J Biol Sci 2020; 16(7):1107-1120. doi:10.7150/ijbs.42109
C-terminal binding proteins 1 and 2 in traumatic brain injury-induced inflammation and their inhibition as an approach for anti-inflammatory treatment
1. Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
2. Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, China
3. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora CO 80045, USA
*These authors contributed equally to this work.
Li H, Zhang C, Yang C, Blevins M, Norris D, Zhao R, Huang M. C-terminal binding proteins 1 and 2 in traumatic brain injury-induced inflammation and their inhibition as an approach for anti-inflammatory treatment. Int J Biol Sci 2020; 16(7):1107-1120. doi:10.7150/ijbs.42109. Available from http://www.ijbs.com/v16p1107.htm
Traumatic brain injury (TBI) induces an acute inflammatory response in the central nervous system that involves both resident and peripheral immune cells. The ensuing chronic neuroinflammation causes cell death and tissue damage and may contribute to neurodegeneration. The molecular mechanisms involved in the maintenance of this chronic inflammation state remain underexplored. C-terminal binding protein (CtBP) 1 and 2 are transcriptional coregulators that repress diverse cellular processes. Unexpectedly, we find that the CtBPs can transactivate a common set of proinflammatory genes both in lipopolysaccharide-activated microglia, astrocytes and macrophages, and in a mouse model of the mild form of TBI. We also find that the expression of these genes is markedly enhanced by a single mild injury in both brain and peripheral blood leukocytes in a severity- and time-dependent manner. Moreover, we were able to demonstrate that specific inhibitors of the CtBPs effectively suppress the expression of the CtBP target genes and thus improve neurological outcome in mice receiving single and repeated mild TBIs. This discovery suggests new avenues for therapeutic modulation of the inflammatory response to brain injury.
Keywords: CtBP, proinflammatory transcription, neuroinflammation, microglia activation, traumatic brain injury