Résumé de thèse : 

Cellular stress can promote responses via the activation of signaling pathways ranging from survival to eliciting the initiation of regulated cell deaths (RCDs) such as necroptosis and apoptosis. While necroptosis is more inflammatory, due to the release of cytokines, chemokines, and damageassociated molecular patterns, apoptosis is considered a less immunogenic cell death modality. To date, there are no inhibitors of necroptosis available in the clinic. Thus, one strategy is to identify inhibitors of necroptosis from already FDA-approved drugs or at least to identify modulators that can dampen the immunogenic signature associated with RCDs, especially in necroptosis conditions. In this context, we have shown that ERK1/2 functions as a pro-death modulator in TNF-induced necroptosis, while displaying a pro-survival role in apoptosis in L929sAhFas cells. Our findings and that of others show that ERK1/2 is involved in necroptosis-activated cell-autonomous functions via the increase of pro-inflammatory cytokines gene expression. Using quantitative ERK signaling dynamics analysis via biosensor imaging, we revealed distinct amplitude- and frequency-modulated (AM/FM) ERK activity signaling dynamics in L929 depending on the triggered cellular process: survival, apoptosis, or necroptosis. We show that inhibition of the characteristic (AM/FM) ERK signaling  dynamics in TNFinduced necroptosis inhibits the gene expression increase of the proinflammatory cytokines TNF and IL-6 during TNF-induced necroptosis in the L929sAhFas cell line. The objectives of the project are 3fold: 1- To identify inhibitors or modulators of necroptosis in FDA-approved drugs to fill the existing gap in the clinical management of necroptosis. 2- To determine the mechanism of action, including the ERK pulse generator, governing the non-canonical engagement of ERK in mediating proinflammatory cytokines gene expression increase during necroptosis. 3- To establish the causality link by investigating the correlation between ERK signaling dynamics and pro-inflammatory gene expression patterns at the single-cell level during necroptosis.

Keywords: Necroptosis, ERK, RSK, inflammation, FDA-approved drugs

Liu, X., Xie, X., Ren, Y., Shao, Z., Zhang, N., Li, L., Ding, X., & Zhang, L. (2021). The role of necroptosis in disease and treatment

. doi.org/10.1002/mco2.108


Directeur(s) de thèse : Franck RIQUET, Benjamin PFEUTY