Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators

• Published in: Glia 2006-05, Vol.53 (7), p.688-695
• Main Authors: Bsibsi, Malika, Persoon-Deen, Carla, Verwer, Ronald W.H., Meeuwsen, Sonja, Ravid, Rivka, Van Noort, Johannes M.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; astrocytes; Astrocytes - drug effects; Astrocytes - immunology; Astrocytes - metabolism; Biological and medical sciences; Cell Survival - drug effects; Cell Survival - immunology; Cells, Cultured; Cytokines - pharmacology; Cytoprotection - drug effects; Cytoprotection - immunology; Down-Regulation - drug effects; Down-Regulation - immunology; Encephalitis - immunology; Encephalitis - metabolism; Encephalitis - physiopathology; Endothelial Cells - drug effects; Endothelial Cells - immunology; Endothelial Cells - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gliosis - immunology; Gliosis - metabolism; Gliosis - physiopathology; Growth Inhibitors - biosynthesis; Growth Inhibitors - immunology; Growth Inhibitors - pharmacology; Growth Substances - biosynthesis; Growth Substances - immunology; Growth Substances - pharmacology; Humans; inflammation; Interleukins - biosynthesis; Interleukins - immunology; Isolated neuron and nerve. Neuroglia; Male; neuroprotection; Neuroprotective Agents - metabolism; Toll-Like Receptor 3 - agonists; Toll-Like Receptor 3 - immunology; Toll-Like Receptor 3 - metabolism; Toll-Like Receptor 4 - agonists; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Up-Regulation - drug effects; Up-Regulation - immunology; Vertebrates: nervous system and sense organs
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.20328

Toll‐like receptors (TLRs) are innate immunity receptors that are expressed on a wide range of cell types, including CNS glial cells. In general, TLR engagement by specific sets of microbial ligands triggers production of pro‐inflammatory factors and enhances antigen‐presenting cell functions. The functional roles of TLR in the CNS, however, are still poorly understood. While adult human astrocytes in culture dominantly express TLR4, they display a strikingly strong and selective induction of TLR3 when activated by pro‐inflammatory cytokines, TLR3 or TLR4 agonists, or oxidative stress. Gene profiling analysis of the astrocyte response to either TLR3 or TLR4 activation revealed that TLR3, but not TLR4, induces expression of a range of neuroprotective mediators and several other molecules that regulate cellular growth, differentiation, and migration. Also, TLR3 triggered enhanced production of anti‐inflammatory cytokines including interleukin‐9 (IL‐9), IL‐10, and IL‐11 and downregulation of the p40 subunit of IL‐12 and IL‐23. The collective TLR3‐induced products were found in functional assays to inhibit astrocyte growth, promote human endothelial cell growth, and importantly, to enhance neuronal survival in organotypic human brain slice cultures. Together, our data indicate that TLR3 is induced on human astrocytes upon inflammation and when activated, mediates a comprehensive neuroprotective response rather than a polarized pro‐inflammatory reaction. © 2006 Wiley‐Liss, Inc.