Interleukin-1β induces a reactive astroglial phenotype via deactivation of the Rho GTPase–Rock axis

GR John, L Chen, MA Rivieccio… - Journal of …, 2004 - Soc Neuroscience
GR John, L Chen, MA Rivieccio, CV Melendez-Vasquez, A Hartley, CF Brosnan
Journal of neuroscience, 2004Soc Neuroscience
The cytokine interleukin-1β (IL-1β) 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-1β 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-1β …
The cytokine interleukin-1β (IL-1β) 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-1β 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-1β 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-1β 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-1β deactivates Rho, and further demonstrated that a constitutively active Rho construct rescued astrocytes from developing an IL-1β-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.
Soc Neuroscience