Wnt5a/Ror2 promotes Nrf2‐mediated tissue protective function of astrocytes after brain injury

Astrocytes, a type of glial cells, play critical roles in promoting the protection and repair of damaged tissues after brain injury. Inflammatory cytokines and growth factors can affect gene expression in astrocytes in injured brains, but signaling pathways and transcriptional mechanisms that regulate tissue protective functions of astrocytes are still poorly understood. In this study, we investigated the molecular mechanisms regulating the function of reactive astrocytes induced in mouse models of stab wound (SW) brain injury and collagenase‐induced intracerebral hemorrhage (ICH). We show that basic fibroblast growth factor (bFGF), whose expression is up‐regulated in mouse brains after SW injury and ICH, acts synergistically with inflammatory cytokines to activate E2F1‐mediated transcription of a gene encoding the Ror‐family protein Ror2, a receptor for Wnt5a, in cultured astrocytes. We also found that subsequent activation of Wnt5a/Ror2 signaling in astrocytes results in nuclear accumulation of antioxidative transcription factor Nrf2 at least partly by increased expression of p62/Sqstm1, leading to promoted expression of several Nrf2 target genes, including heme oxygenase 1. Finally, we provide evidence demonstrating that enhanced activation of Wnt5a/Ror2 signaling in astrocytes reduces cellular damage caused by hemin, a degradation product of hemoglobin, and promotes repair of the damaged blood brain barrier after brain hemorrhage. Main Points bFGF and inflammatory cytokines cooperatively activate Wnt5a/Ror2‐Nrf2 axis in astrocytes. Wnt5a/Ror2‐Nrf2 axis is activated in reactive astrocytes induced after brain hemorrhage and promotes repair of the damaged blood brain barrier.