Interleukin-1beta induces a reactive astroglial phenotype via deactivation of the Rho GTPase-Rock axis.
The cytokine interleukin-1beta (IL-1beta) is critical to the formation of an astrocytic scar after CNS injury, but the mechanisms by which it induces a reactive phenotype remain unresolved. Here, we show that IL-1beta regulates the phenotype of astrocytes via deactivation of the Rho GTPase-Rho kinase (ROCK) pathway, which governs cellular morphology and migration via effects on F-actin and its interactions with focal adhesions, nonmuscle myosin, and microvillar adapter proteins of the ezrin-radixin-moesin (ERM) family. We found that IL-1beta induced cortical reorganization of F-actin and dephosphorylation of focal adhesion kinase, myosin light chain 2, and myosin phosphatase targeting subunit 1 in primary human astrocytes, and that all of these effects were mimicked by Rho-ROCK pathway blockade. We also found that IL-1beta conversely potentiated ERM phosphorylation, and that this effect was mediated via a Rho-ROCK-independent mechanism. Next, we used a rhotekin pulldown assay to confirm directly that IL-1beta deactivates Rho, and further demonstrated that a constitutively active Rho construct rescued astrocytes from developing an IL-1beta-induced reactive phenotype. These data implicate cytokine regulation of the Rho-ROCK pathway in the generation of a reactive astrogliosis, and we suggest that interventions targeted at this level may facilitate manipulation of the glial scar in inflammatory disorders of the human CNS.
John
Gareth R
GR
Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. gareth.john@mssm.edu
Chen
Lanfen
L
Rivieccio
Mark A
MA
Melendez-Vasquez
Carmen V
CV
Hartley
Adam
A
Brosnan
Celia F
CF
D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D022001:Focal Adhesions / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054460:rho-Associated Kinases
D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins