Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators.
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.
Division of Biomedical Research, TNO Quality of Life, Leiden, The Netherlands.
Malika
M
Bsibsi
Carla
C
Persoon-Deen
Ronald W H
RW
Verwer
Sonja
S
Meeuwsen
Rivka
R
Ravid
Johannes M
JM
Van Noort
D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004660:Encephalitis / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D005911:Gliosis / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D006133:Growth Substances / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D018696:Neuroprotective Agents / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D006131:Growth Inhibitors; D006133:Growth Substances; D007378:Interleukins; D018696:Neuroprotective Agents; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4