Activation of innate immune pathways after brain injury promotes scar formation and impairs tissue recovery

Scar formation is a major hindrance to central nervous system regeneration upon traumatic injury. Glial cells are key players during the wound healing process, and their reaction to injury determines the extent of tissue restoration. Here, we used the regenerative potential of the zebrafish telencephalon to identify specific molecular and cellular mechanisms regulating glial scar formation. We demonstrated that contact of the cerebrospinal fluid with the brain parenchyma after injury activates toll-like receptor 2 (Tlr2) and the chemokine receptor 3 (Cxcr3) innate immunity pathways leading to initiation of a glial scar. These pathways were critical for scarring even after ablation of microglia and infiltrating monocytes. Our data support a specific role for the injury-induced Tlr1/2 and Cxcr3 signaling pathways in controlling proliferation of the oligodendrocyte progenitors and therefore exacerbated glial reactivity, contributing to scar formation. Interference with the Tlr1/2 and Cxcr3 pathways after injury alleviated glial scar formation and improved tissue restoration. We performed gene expression microarray analysis in the whole telencephalon at different time points during the course of regeneration after nostril or skull brain injury