Genetic manipulation of NEMO reveals glial cell type-specific effects of NF-κB activation following brain injury Esther Engelhardt1, Jana Göbel1, Hannah M. Jahn1, Matteo Bergami1,2 1CECAD Cologne, Germany; 2CMMC Cologne, Germany
Glial cells have recently emerged as important players in a host of brain diseases. In particular, neurodegenerative diseases characterized by a strong inflammatory component are invariably accompanied by a prominent reactivity of microglia and astrocytes, as following traumatic and ischemic brain injury. Typical hallmarks of glial reactivity include hypertrophy, polarization, up-regulation of certain markers and cell proliferation which are all believed to contribute to scar formation and regulate tissue repair within the injured area. However, the molecular pathways involved in both initiating and maintaining this reactivity state are poorly characterized. Here, we asked the key questions whether and how the canonical NF-κB pathway, i.e. one of the most prominent pathways known to regulate tissue inflammatory responses, plays a role in astrocyte and microglia cell reactivity during brain injury. To this aim, we utilized a recently generated knock-in mouse line expressing a GFP-labelled p65 (NF-κB subunit) and monitored NF-κB nuclear translocation following controlled cortical stab-wound (SW) injury in vivo. NF-κB activation was found to be mostly restricted to microglia and astrocytes, although with markedly distinct temporal dynamics. In particular, NF-κB-mediated astrocyte activation appeared surprisingly delayed compared to microglia, suggesting that astroglial cells mostly contribute to later stages of the inflammatory response. On the other side, microglia displayed p65 nuclear translocation as early as 1h after injury. In an effort to reveal the selective contribution of this temporally shifted activation of NF-κB, we generated two mouse lines to conditionally ablate the master regulator of NF-κB activation (NEMO) either in microglia or astrocytes during injury. Time course analysis revealed differential changes in proliferation and survival of each of the cell types upon deletion of NEMO, thus suggesting their preferential contribution to distinct temporal phases of the inflammatory response.
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