Lee, S., Park, J.Y., Lee, W.H., Kim, H., Park, H.C., Mori, K., and Suk, K. (2009) Lipocalin-2 is an autocrine mediator of reactive astrocytosis. The Journal of neuroscience : the official journal of the Society for Neuroscience. 29(1):234-249.
Astrocytes, the most abundant glial cell type in the brain, provide metabolic and trophic support to neurons and modulate
synaptic activity. In response to a brain injury, astrocytes proliferate and become hypertrophic with an increased expression
of intermediate filament proteins. This process is collectively referred to as reactive astrocytosis. Lipocalin 2 (lcn2) is
a member of the lipocalin family that binds to small hydrophobic molecules. We propose that lcn2 is an autocrine mediator
of reactive astrocytosis based on the multiple roles of lcn2 in the regulation of cell death, morphology, and migration of
astrocytes. lcn2 expression and secretion increased after inflammatory stimulation in cultured astrocytes. Forced expression
of lcn2 or treatment with LCN2 protein increased the sensitivity of astrocytes to cytotoxic stimuli. Iron and BIM (Bcl-2-interacting
mediator of cell death) proteins were involved in the cytotoxic sensitization process. LCN2 protein induced upregulation of
glial fibrillary acidic protein (GFAP), cell migration, and morphological changes similar to characteristic phenotypic changes
termed reactive astrocytosis. The lcn2-induced phenotypic changes of astrocytes occurred through a Rho–ROCK (Rho kinase)–GFAP
pathway, which was positively regulated by nitric oxide and cGMP. In zebrafishes, forced expression of rat lcn2 gene increased
the number and thickness of cellular processes in GFAP-expressing radial glia cells, suggesting that lcn2 expression in glia
cells plays an important role in vivo. Our results suggest that lcn2 acts in an autocrine manner to induce cell death sensitization and morphological changes in
astrocytes under inflammatory conditions and that these phenotypic changes may be the basis of reactive astrocytosis in vivo.