A Pvr–AP-1–Mmp1 signaling pathway is activated in astrocytes upon traumatic brain injury

Abstract

AbstractTraumatic brain injury (TBI) caused by external mechanical forces is a major health burden worldwide, but the underlying mechanism in glia remains largely unclear. We report herein thatDrosophilaadults exhibit a defective blood-brain-barrier (BBB), elevated innate immune responses, and hypertrophy of astrocytes upon consecutive strikes with a high-impact trauma device. RNA sequencing (RNA-seq) analysis of these astrocytes revealed upregulated expression of genes encoding PDGF and VEGF receptor-related (Pvr, a receptor tyrosine kinase (RTK)), adaptor protein complex 1 (AP-1, a transcription factor complex of the c-Jun N-terminal Kinase (JNK) pathway) composed of Jun-related antigen (Jra) and kayak (kay), and matrix metalloproteinase 1 (Mmp1) following TBI. Interestingly, Pvr is both required and sufficient for AP-1 and Mmp1 upregulation, while knockdown of AP-1 expression in the background of Pvr overexpression in astrocytes rescued Mmp1 upregulation upon TBI, indicating that Pvr acts as the upstream receptor for the downstream AP-1–Mmp1 transduction. Moreover, dynamin-associated endocytosis was found to be an important regulatory step in downregulating Pvr signaling. Our results identify a new Pvr–AP-1–Mmp1 signaling pathway in astrocytes in response to TBI, providing potential targets for developing new therapeutic strategies of TBI.Main PointsThe study provided RNA-seq data of astrocytes following traumatic brain injury (TBI)Genes involved in endocytic trafficking are upregulated in astrocytes after TBIA new Pvr–AP-1–Mmp1 pathway is activated in astrocytes following TBI.Inhibition of endocytosis in astrocytes upregulates the Pvr–AP-1–Mmp1 signaling.