Traumatic Brain Injury Activates a Pvr-AP-1-Mmp1 Signaling Pathway in Astrocytes

Główne pojęcia

Traumatic brain injury activates a Pvr-AP-1-Mmp1 signaling pathway in astrocytes, leading to astrocyte swelling, blood-brain barrier disruption, and innate immune response.

Streszczenie

The study used a Drosophila model of traumatic brain injury (TBI) induced by a high-impact trauma (HIT) device. The key findings are:

TBI caused multiple defects in Drosophila adults, including blood-brain-barrier (BBB) and blood-eye-barrier (BEB) disruption, elevated innate immune responses, and astrocyte swelling.

RNA sequencing analysis of astrocytes revealed upregulated expression of genes encoding the receptor tyrosine kinase Pvr, the AP-1 transcription factor complex, and the matrix metalloproteinase Mmp1 following TBI.

Pvr is both required and sufficient for AP-1 and Mmp1 upregulation. Knockdown of AP-1 expression in the background of Pvr overexpression rescued Mmp1 upregulation, indicating that Pvr acts as the upstream receptor for the downstream AP-1–Mmp1 pathway.

Dynamin-associated endocytosis was found to be an important regulatory step in downregulating Pvr signaling. Inhibition of endocytosis in astrocytes upregulated the Pvr–AP-1–Mmp1 signaling.

The study identifies a new Pvr–AP-1–Mmp1 signaling pathway in astrocytes that is activated in response to TBI, providing potential targets for developing new therapeutic strategies.

Statystyki

"About 43% of people discharged after hospitalization for acute TBI develop long-term locomotor disability."
"Drosophila adults exhibit a defective blood-brain-barrier (BBB), elevated innate immune responses, and astrocyte swelling upon consecutive strikes with a high-impact trauma device."
"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."
"Inhibition of endocytosis in astrocytes upregulates the Pvr–AP-1–Mmp1 signaling."

Cytaty

"Traumatic brain injury (TBI) caused by external mechanical forces is a major health burden worldwide, but the underlying mechanism in glia remains largely unclear."
"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."

Kluczowe wnioski z

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

by Li,T., Shi,W... o www.biorxiv.org 03-28-2023

https://www.biorxiv.org/content/10.1101/2023.03.27.534488v2

Głębsze pytania

How might the Pvr-AP-1-Mmp1 signaling pathway be targeted therapeutically to improve outcomes in TBI patients

The Pvr-AP-1-Mmp1 signaling pathway identified in astrocytes following TBI presents a promising target for therapeutic interventions to improve outcomes in TBI patients. One potential therapeutic approach could involve modulating the activity of Pvr, the upstream receptor in this pathway. By targeting Pvr with specific agonists or antagonists, it may be possible to regulate the downstream activation of AP-1 and Mmp1, thereby modulating the inflammatory and tissue remodeling responses associated with TBI. Additionally, targeting the AP-1 transcription factor complex or Mmp1 directly could also be explored as potential therapeutic strategies. By understanding the molecular mechanisms of this signaling pathway, researchers could develop targeted therapies that aim to reduce neuroinflammation, promote tissue repair, and enhance recovery following TBI.

What other signaling pathways or cellular processes in astrocytes might be involved in the response to TBI beyond the Pvr-AP-1-Mmp1 axis

Beyond the Pvr-AP-1-Mmp1 axis, several other signaling pathways and cellular processes in astrocytes may play crucial roles in the response to TBI. One such pathway is the JNK signaling pathway, which is known to be involved in various cellular processes, including cell migration, organ size control, and cell death. The activation of JNK signaling in astrocytes following TBI could contribute to the regulation of inflammatory responses, tissue remodeling, and cell survival. Additionally, the activation of innate immune pathways, such as the Toll and Imd pathways, may also play a significant role in the astrocytic response to TBI. These pathways are essential for mounting an immune response to injury and infection, and their dysregulation could impact the outcome of TBI. Furthermore, the involvement of endocytic trafficking genes, as observed in the RNA-seq analysis, suggests that the regulation of vesicle trafficking and membrane dynamics in astrocytes could be critical for their response to TBI.

Given the evolutionary conservation of astrocyte function, how might the insights from this Drosophila study translate to understanding astrocyte responses in mammalian TBI models or human patients

The insights gained from this Drosophila study on astrocyte responses to TBI could have significant implications for understanding astrocyte function in mammalian TBI models and human patients. Astrocytes are highly conserved across species, and many fundamental cellular processes and signaling pathways are shared between Drosophila and mammals. Therefore, the identification of the Pvr-AP-1-Mmp1 signaling pathway in astrocytes in response to TBI in Drosophila could provide valuable insights into similar pathways that may be activated in mammalian astrocytes following TBI. By studying the molecular mechanisms and functional consequences of this pathway in Drosophila, researchers can gain a deeper understanding of how astrocytes respond to injury in mammals. This knowledge could potentially lead to the development of novel therapeutic strategies for TBI patients by targeting similar pathways in human astrocytes to modulate inflammation, promote tissue repair, and improve neurological outcomes.