PI: T. Wirth

In the second funding period, we performed comprehensive gene expression profiling after closed head traumatic brain injury (TBI) using RNA-seq and determined a prominent correlation between hematoma formation and overall post-traumatic gene expression changes. IKK/NF-κB signaling in astrocytes was identified as a critical regulator of diverse neuroimmune reactions including a specific astrocyte/microglia interplay which promotes phagocytosis-proficient microglia polarization and efficient amyloid plaque clearance. We also gained insights how IKK/NF-κB signaling in astrocytes may interfere with the integrity of the blood- brain-barrier (BBB) after TBI and established a new mouse model of repetitive mild brain injury phenocopying features of chronic traumatic encephalopathy. Interestingly, mice with IKK/NF-κB activation in oligodendro- cytes develop a spontaneous neuroinflammatory phenotype with aggravated stress and immune signaling as well as cellular senescence leading to demyelination and behavioral deficits. Therefore, in the third funding period we will characterize to which extent TBI-mediated IKK/NF-κB activation in oligodendrocytes promotes stress and post-mitotic senescence processes and how this is linked to myelin loss. Our current data also implicate that the IKK/NF-κB signaling system in different glia cells acts as a central hub in the regulation of post-traumatic immune responses in the CNS. This possibly includes the communication with peripheral immune cells and organs. As TBI patients frequently suffer from subsequent infections and other systemic complications, we will not only address the impact of IKK/NF-κB signaling in glia cells on the immune crosstalk within the CNS but in addition the bidirectional communication between CNS and peripheral immune system. In particular, we want to identify relevant cellular and soluble players as well as effectors important for systemic immune dysfunction after TBI. In this context, we will also focus on the role of IKK/NF-κB signaling in astrocytes on the post-traumatic restoration of the BBB using non-invasive MRI and PET analyses.