Extracellular HSP27 mediates angiogenesis through Toll-like receptor 3

Dominique Thuringer, Gaetan Jego, Guillaume Wettstein, Olivier Terrier, Laurent Cronier, Nadhir Yousfi, Sophie Hébrard, André Bouchot, Adonis Hazoumé, Anne Laure Joly, Martin Gleave, Manuel Rosa-Calatrava, Eric Solary, Carmen Garrido

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    90 Citations (Scopus)

    Abstract

    The heat-shock protein 27 (HSP27) is up-regulated in tumor cells and released in their microenvironment. Here, we show that extracellular HSP27 has a proangiogenic effect evidenced on chick chorioallantoic membrane. To explore this effect, we test the recombinant human protein (rhHSP27) at physiopathological doses (0.1-10 μg/ml) onto human microvascular endothelial cells (HMECs) grown as monolayers or spheroids. When added onto HMECs, rhHSP27 dosedependently accelerates cell migration (with a peak at 5 μg/ml) and favors spheroid sprouting within 12-24 h. rhHSP27 increases VEGF gene transcription and promotes secretion of VEGF-activating VEGF receptor type 2. Increased VEGF transcription is related to NF-κB activation in 30 min. All of these effects are initiated by rhHSP27 interaction with Toll-like receptor 3 (TLR3). Such an interaction can be detected by immunoprecipitation but does not seem to be direct, as we failed to detect an interaction between rhHSP27 and monomeric TLR3 by SPR analysis. rhHSP27 is rapidly internalized with a pool of TLR3 to the endosomal compartment (within 15-30 min), which is required for NF-kB activation in a cytosolic Ca2+ dependent manner. The HSP27/TLR3 interaction induces NF-κB activation, leading to VEGF-mediated cell migration and angiogenesis. Such a pathway provides alternative targets for antiangiogenic cancer therapy.

    Original languageEnglish
    Pages (from-to)4169-4183
    Number of pages15
    JournalFASEB Journal
    Volume27
    Issue number10
    DOIs
    Publication statusPublished - 1 Oct 2013

    Keywords

    • Autocrine VEGFR2 activation
    • Chorioallantoic membrane
    • Endocytosis
    • Microvascular endothelial cell
    • NF-κB pathway
    • Tubulogenesis
    • VEGF release

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