Lipocalin-2 is an autocrine mediator of reactive astrocytosis.
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.
Lee
Shinrye
S
Department of Pharmacology, Brain Science and Engineering Institute, Cell Matrix Research Institute, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
Park
Jae-Yong
JY
Lee
Won-Ha
WH
Kim
Ho
H
Park
Hae-Chul
HC
Mori
Kiyoshi
K
Suk
Kyoungho
K
D000577:Amides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017306:Annexin A2 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects*; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian; D005434:Flow Cytometry / Q000379:methods; D049452:Green Fluorescent Proteins / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D009573:Nitrites / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010586:Phagocytes / Q000187:drug effects / Q000502:physiology; D011419:Propidium; D011725:Pyridines / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015027:Zebrafish; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000577:Amides; D017306:Annexin A2; D009573:Nitrites; D011725:Pyridines; C110881:S-nitro-N-acetylpenicillamine; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C108830:Y 27632; D049452:Green Fluorescent Proteins; D009599:Nitroprusside; D011419:Propidium; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D020741:rho GTP-Binding Proteins; C022616:thiazolyl blue; D010396:Penicillamine; D013755:Tetradecanoylphorbol Acetate