A3: Consequences of cell-type-specific NF-кB modulation for the outcome of traumatic brain injury
PI: T. Wirth
Traumatic brain injury (TBI) represents a leading cause of mortality and morbidity worldwide. Subsequent to the primary impact causing TBI secondary pathology develops over minutes to weeks that includes different metabolic, biochemical, molecular and cellular events not fully understood to date, which ultimately result in additional tissue damage. Survivors of TBI may suffer from lifelong disabling changes in physical, cognitive, and psychosocial functions. Importantly, the secondary pathology is critical in determining the patient outcome. Therefore the exact understanding of the underlying mechanisms is of high interest in order to improve therapeutic interventions. Although TBI is a complex process that, depending on the cause and severity may involve distinct pathomechanisms, a rather common aspect is the posttraumatic development of a neuroinflammatory response. The NF-κB signalling pathway represents the main inflammation-mediating signalling pathway in mammalian cells. It is induced in multiple cell types including parenchymal cells, in endothelial and immune cells as well as in other interacting cells upon traumatic brain injury induction. Importantly, inflammatory cytokines like TNFα and IL-1β are not only target genes of NF-κB, but they again activate the pathway resulting in a potentially selfperpetuating vicious cycle. Although the majority of available data suggest that the NF-κB-driven inflammatory response is largely injury aggravating, possible protective aspects especially during later phases of the injury response have also been suggested. NF-κB is activated in different cell types including neurons, glial cells, endothelial cells, and also infiltrating immune cells. At present it is unclear, whether NF-κB might have distinct functions in these different cell types. This is a critical issue given that the functions of NF-κB in addition to being a proinflammatory regulator also involve aspects like regulation of cell survival and learning and memory. Therefore our hypothesis is that depending on the cell type NF-κB activation has divergent functions in the pathophysiology of TBI. We assume a mainly inflammatory and predominantly detrimental effect of NF-κB in astrocytes and in microglia, whereas we expect a beneficial protective role in neurons and potentially oligodendrocytes.
Traumatic brain injury induces microglia (Iba1) and astroglia (GFAP) activation in the area surrounding the primary insult (ipsi). Expression of the NF-κB dependent target gene Lipocalin 2 (Lcn2) is restricted to the brain region in close proximity of the mechanical damage (ipsi).