Michel Salzet (Presenter)
Laboratoire PRISM U1192, INSERM
Bio: Since 1998, Professor Michel Salzet is the director of the PRISM (http://www.laboratoire-prism.fr). After his PhD, Pr. Salzet worked as Associate Researcher at the Institute of Neurosciences at Stony Brook University (USA), and was subsequently nominated as Senior Research Scientist at the Beth Israel, Mind Body Institute of Harvard Medical School . He became a member of the Institut Universitaire de France.. Pr. M. Salzet is member since 2009 of the core group of European Science Foundation and member of management committee of the forward looks in Personalized Medicine for the European Citizen. From 2009 to 2012, he has been nominated at the CNRS as a scientific delegate. Pr. Salzet has published 274 publications, 27book chapters, 10 patents (H Factor: 54). He was invited in 88 international conference. Pr. Salzet is also co-founder of the Start-Up IMABIOTECH.
Authorship: Duhamel M , Rodet F ,Vanden Abeele F, Wisztorski M , Fournier I, Salzet M
Laboratoire PRISM, U1192 Inserm, University Lille, 59000 Lille
The prohormone convertase 1/3 (PC1/3) is an enzyme playing an important role in the processing within the regulated secretory pathway in the nervous system. We showed by proteomic that PC1/3 is implicated un innate immunity. We demonstrated that PC1/3 inactivated macrophages express an M1-like phenotype, pro-inflammatory chemokines and cytokines secretion and TLR4 Myd88 dependent signaling activation. Under LPS/taxol challenge, PC1/3 KO cells secrete through store-operated calcium entry increase, a cocktail of pro-inflammatory factors including DAMPS. This secreted factors have been shown to favors Th1 response and inhibit viability and resistance of breast and ovarian cancer cells. This strategy can be used as a potential immune therapy for awaking intratumoral macrophages.
he prohormone convertase 1/3 (PC1/3) is an enzyme playing an important role in the processing within the regulated secretory pathway in the nervous system. Recently, a possible implication of PC1/3 in innate immunity has been highlighted. These studies have reported a role of PC1/3 in Toll-like receptor immune response in macrophages. A dysfunctional phenotype characterized by uncontrolled cytokine secretion without stimulation has been observed in PC1/3 knock-out mice and in NR8383 macrophages cell line.
Here, using lentivirus strategy, we investigated the consequences of PC1/3 down-regulation in NR8383 on the intracellular impact and its biological application to cancer therapy. A proteomic approach (shotgun and FASP) has been undertaken in order to obtain a global vision of secreted and cellular proteins overtime. Results were validated by 3D mixed spheroids macrophages/glioma, ELISA and confocal microscopy.
Under sterile conditions, we demonstrated that PC1/3 inactivated macrophages express an M1-like phenotype characterized by filopodia extensions, pro-inflammatory chemokines and cytokines secretion (IL-6, CXCL10, TNF-α) and TLR4 Myd88 dependent signaling activation.
Under LPS challenge, PC1/3 KO cells secrete through store-operated calcium entry increase, a cocktail of pro-inflammatory factors including alarmins and chemokines. This secreted factors have been shown to attract naïve T helper lymphocytes (Th0) which favors cytotoxic response. These factors are also able to inhibit viability and resistance of breast and ovarian cancer cells (SKBR3 and SKOV3). Under inhibitory conditions using IL-10, PC1/3 KO cells still continue to produce inflammatory cytokines.
Conclusions & Discussion
These data established that inhibition of PC1/3 increase pro-inflammatory response giving an M1-like phenotype to macrophages. This strategy may be used as a potential immune therapy for awaking intratumoral macrophages.
References & Acknowledgements:
This research was supported by grants from the Ministère de L’Education Nationale, de L’Enseignement Supérieur et de la Recherche, ANR , Région Nord-Pas de Calais ARCIR, the Université de Lille, SIRIC ONCOLille (IF, MD), Grant INCa-DGOS-Inserm 6041aa, and INSERM.
IP Royalty: no
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