NF-?B activation in astrocytes critically affects wound regeneration after traumatic brain injury
Traumatic brain injury (TBI) is a complex condition in which multiple pathophysiological mechanisms influence the course of the disease. After the primary mechanical impact, neuroinflammatory reactions of glial cells along with infiltrating peripheral immune cells mainly determine the overall clinical outcome. However, these secondary processes and their molecular determinants promoting either beneficial or detrimental consequences are not well-defined. Here, we show that TBI-mediated NF-?B activation in astrocytes impairs their homeostatic functions and acts as a key regulator of multiple post-traumatic responses in mice. We determined striking deficits in CNS scar formation after TBI using a combination of NF-?B-reporter mice, conditional mouse models allowing astrocytic NF-?B modulation, and analysis of transcriptomic signatures. Importantly, the development of wound healing deficits depends on paracrine signaling of NF-?B-activated astrocytes and cross-responsive microglial cells. Our findings identify astrocytic NF-?B activation as a critical pathological amplification factor interfering with the restoration of CNS integrity at wound lesion sites. Overall design: To further analyzed the impact of astrocytic IKK/NF-kappaB modulation on the post-traumatic transcriptome using an IKK2 gain-of-function (GoF) and IKK2 loss-of-function (LoF) mouse model