Infectious Diseases Forum: Dr. Philippe PIERRE
Date / Heure
Date(s) - 17/06/2019
11 h 30 min - 12 h 30 min
Amphi Pasteur, Tour CERVI
Dr. Philippe PIERRE (Directeur du CIML – Marseille-Luminy), “ Are the integrated stress response and translation oscillation required to optimize innate responses to pathogens ? ”
Endoplasmic Reticulum (ER) stress triggers or amplifies inflammatory signals and cytokines production in immune cells. The inducible phosphatase 1 co-factor GADD34/PPP1R15A, that selectively mediates eIF2a-P dephosphorylation after ER-stress has been shown to regulate pro-inflammatory cytokines and interferon expression in dendritic cells (DCs). GADD34 expression is required for IFN synthesis upon cytosolic dsRNA sensing by fibroblasts and we provide further evidence that production of type-I IFN is linked to cell’s ability to enter PKR dependent-translational arrest and then overcome this inhibition by decreasing eIF2α phosphorylation through GADD34 expression. We also investigated how pharmacological interference with the eIF2a-P pathway can be beneficial for the treatment of immune pathological conditions, such as type-I interferon-dependent auto-inflammatory diseases. Recently, several amino-guanidines compounds, such as guanabenz (GBZ), have been shown to perturb the eIF2a phosphorylation-dephosphorylation cycle, and using both mouse and human DCs, as well as B cells, we show that GBZ prevents endosomal toll-like-receptor 9 (TLR9) activation by CpG ODN or DNA-Immunoglobulin Complexes. In vivo, GBZ treatment protects mice from CpG-dependent cytokine shock and decreases anti-nucleic acid auto-antibodies production in the TMPD-induced systemic lupus erythematosus mode.
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