Institut de recherche biomédicale
     

    Project 3

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    Characterization of the molecular mechanisms controlling inflammation

     

    Principal Investigator : Cécile Arrieumerlou

    cecile.arrieumerlou@inserm.fr
    Phone : 01 40 51 64 76


    The group

    Milica Milivojevic, BioSPC PhD student
    Anne-Sophie Dangeard, engineer

     

    Objective

     

    The ability of a host organism to mount an innate immune response to bacterial infections is critical. Epithelial cells play a critical role in this process. They act as sentinels of the immune system, and largely contribute with macrophages to the secretion of factors that orchestrate inflammation and limit the dissemination of bacteria in infected tissues. Our goal is to understand the cellular and molecular mechanisms that control the inflammatory response of epithelial cells during a bacterial infection.

     

    Research interests


    Our laboratory discovered that a mechanism of cell-cell communication potentiates the innate immune response of epithelial cells during infection by enteroinvasive bacteria including Shigella flexneri, Listeria monocytogenes and Salmonella typhimurium. We showed that communication between infected and uninfected bystander cells circumvents the immunosuppressive activity of Shigella flexneri bacteria, and amplifies the secretion of inflammatory cytokines near the sites of infection. By monitoring inflammatory signals at the single-cell level, we found that the activation of the transcription factor NF-kB and MAP kinases JNK, ERK and p38 rapidly propagates from infected to uninfected bystander cells, leading to massive IL-8 and TNFa expression in the latter. Cell-cell contacts are required to transmit inflammatory signals and amplify the expression of pro-inflammatory cytokines. In addition, this mechanism is inhibited by gap junction inhibitors and absent in cells that do not express connexins. In contrast, cell-cell communication is massively enhanced when connexin43 is overexpressed, strongly indicating that cell-cell communication is gap junction-mediated. These findings were published in Immunity and highlighted in Nature Reviews Immunology.

    We now aim at characterizing the signalling pathways underlying the process of cell-cell communication by identifying the proteins involved in infected and bystander cells, as well as the small molecules that diffuse via gap junctions.


    Publications

     

    Artner D, Oblak A, Ittig S, Garate JA, Horvat S, Arrieumerlou C, Hofinger A, Oostenbrink C, Jerala R, Kosma P, Zamyatina A. Conformationally Constrained Lipid A Mimetics for Exploration of Structural Basis of TLR4/MD-2 Activation by Lipopolysaccharide. ACS Chem Biol. 2013 8(11):2423-32.

    Reiterer, V., Grossniklaus, L., Tschon, T., Kasper, C. A., Sorg, I. and Arrieumerlou C. Shigella flexneri type III secreted effector OspF reveals new crosstalks of proinflammatory signaling pathways during bacterial infection. Cell Signal. 2011 Jul; 23(7):1188-96.

    Kasper, C. A., Sorg, I., Schmutz, C., Tschon, T., Wischnewski, H., Kim, M. L. and Arrieumerlou, C. (2010). Cell-Cell Propagation of NF-kappaB Transcription Factor and MAP Kinase Activation Amplifies Innate Immunity against Bacterial Infection. Immunity, 33(5), 804–816.

    Kim, M. L., Jeong, H. G., Kasper, C. A. and Arrieumerlou, C. (2010). IKKalpha Contributes to Canonical NF-kappaB Activation Downstream of Nod1-Mediated Peptidoglycan Recognition. PLoS One, 5(10), e15371.


    Financial supports

    This project is supported by the Swiss National fund and INSERM.