Wnt5a-Ror2 signaling activates p62-Nrf2 axis in reactive astrocytes after brain injury

Abstract

In the brains under pathological conditions, astrocytes become reactive astrocytes that exhibit various context-dependent functions through the regulation of specific signaling pathways and transcriptional mechanisms in response to environmental changes. Reactive astrocytes induced in injured brains begin proliferating and play a role in promoting protection and repair of damaged tissues, but the relationship between the proliferative characteristics and tissue-protective and repair functions of reactive astrocytes remains unclear. Here, we show that growth factor signaling elicited by bFGF and HB-EGF, whose expression is up-regulated in the injured brains, acts synergistically with inflammatory cytokine signaling in astrocytes, thereby markedly up-regulating gene expression of the Ror-family protein Ror2, a receptor for Wnt5a. Activation of Wnt5a-Ror2 signaling in astrocytes results in intracellular accumulation of phosphorylated p62, thereby activating antioxidative transcription factor Nrf2. Finally, we provide evidence demonstrating that forced activation of Wnt5a-Ror2-p62-Nrf2 signaling axis 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.