TLR2 hypersensitivity of astrocytes as functional consequence of previous inflammatory episodes

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The Journal of Immunology. 2011, 186(5), pp. 3237-3247. ISSN 0022-1767. eISSN 1550-6606. Available under: doi: 10.4049/jimmunol.1002787
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Precedent inflammatory episodes may drastically modify the function and reactivity of cells. We investigated whether priming of astrocytes by microglia-derived cytokines alters their subsequent reaction to pathogen-associated danger signals not recognized in the quiescent state. Resting primary murine astrocytes expressed little TLR2, and neither the TLR2/6 ligand fibroblast-stimulating lipopeptide-1 (FSL1) nor the TLR1/2 ligand Pam(3)CysSK(4) (P3C) triggered NF-κB translocation or IL-6 release. We made use of single-cell detection of NF-κB translocation as easily detectable and sharply regulated upstream indicator of an inflammatory response or of c-Jun phosphorylation to measure restimulation events in astrocytes under varying conditions. Cells prestimulated with IL-1β, with a TLR3 ligand, with a complete cytokine mix consisting of TNF-α, IL-1β, and IFN-γ, or with media conditioned by activated microglia responded strongly to FSL1 or P3C stimulation, whereas the sensitivity of the NF-κB response to other pattern recognition receptors was unchanged. This sensitization to TLR2 ligands was associated with an initial upregulation of TLR2, displayed a "memory" window of several days, and was largely independent of the length of prestimulation. The altered signaling led to altered function, as FSL1 or P3C triggered the release of IL-6, CCL-20, and CXCL-2 in primed cells, but not in resting astrocytes. These data confirmed the hypothesis that astrocytes exposed to activated microglia assume a different functional phenotype involving longer term TLR2 responsiveness, even after the initial stimulation by inflammatory mediators has ended.

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ISO 690HENN, Anja, Susanne KIRNER, Marcel LEIST, 2011. TLR2 hypersensitivity of astrocytes as functional consequence of previous inflammatory episodes. In: The Journal of Immunology. 2011, 186(5), pp. 3237-3247. ISSN 0022-1767. eISSN 1550-6606. Available under: doi: 10.4049/jimmunol.1002787
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@article{Henn2011-03-01hyper-18152,
  year={2011},
  doi={10.4049/jimmunol.1002787},
  title={TLR2 hypersensitivity of astrocytes as functional consequence of previous inflammatory episodes},
  number={5},
  volume={186},
  issn={0022-1767},
  journal={The Journal of Immunology},
  pages={3237--3247},
  author={Henn, Anja and Kirner, Susanne and Leist, Marcel}
}
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