Many human diseases, including cancer, share an inflammatory component but the molecular underpinnings remain incompletely understood. We report that physiological and pathological Dickkopf1 (DKK1) activity fuels inflammatory cytokine responses in cell models, mice and humans. DKK1 maintains the elevated inflammatory tone of cancer cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors. DKK1- controlled inflammation derives from cell-autonomous mechanisms, which involve SOCS3- restricted, nuclear RelA (p65) activity. We translate these findings to humans by showing that genetic DKK1 variants are linked to elevated cytokine production across healthy populations. Finally, we find that genetic deletion of DKK1 but not pharmacological neutralization of soluble DKK1 ameliorates inflammation and disease trajectories in a mouse model of endotoxemia. Collectively, our study identifies a cell-autonomous function of DKK1 in the control of the inflammatory response, which is conserved between malignant and nonmalignant cells. Additional studies are required to mechanistically dissect cellular DKK1 trafficking and signaling pathways.

Les douleurs neuropathiques désignent une hypersensibilité du système nerveux central sensoriel. C’est une maladie chronique et handicapante qui touche environ 6% de la population française. Cependant, à l’heure actuelle, il n’existe pas de traitement spécifique et efficace. Dans le cadre de cette thèse, nous avons utilisé deux stratégies différentes afin de développer des outils pharmacologiques originaux pour traiter ces douleurs : une approche phénotypique autour de deux inhibiteurs de la surproduction de TNFα (un dérivé de 2-aminopyrimidine et un dérivé de pyridin-2-yl guanidine) et une approche moléculaire autour du MY 5445 (un inhibiteur de PDE5 dérivé de phtalazine). En particulier, notre travail s’est basé sur la conception, la synthèse et l’étude des relations structure-activité autour de ces différents hits et nous avons obtenu des composés efficaces par voie i.p. ou per-os sur un modèle murin de douleurs neuropathiques.En parallèle de ce travail de pharmacologie, nous avons développé différents systèmes catalytiques (Pd, Cu) en milieu micellaire afin de former des liaisons C-N à température quasi-ambiante. / Neuropathic pains correspond to a central sensory nervous system hypersensitivity. It is a chronic and disabling disease, which touch around 6% of the French population. Nowadays, there is no specific and efficient treatment. In my PhD project, we used two different strategies in order to develop innovative pharmacological tools to treat those pains: a phenotypic approach around two TNFα overproduction inhibitor (a 2-aminopyrimidine derivative and a pyridin-2-yl guanidine derivative) and a molecular approach around MY 5445 (a phthalazine PDE5 inhibitor). Our work was based on the design, synthesis and structure-activity relationship study around various hits and we obtained compounds i.p. and orally effective on a murin neuropathic pain model.In parallel to this pharmacological work, we developed different catalytic systems (Pd, Cu) under micellar conditions to form C-N bonds at almost room temperature.