Abstract
Macrophages are heterogeneous cell mediators, which play a crucial role in inflammation. A chemical molecule ABX has been developed by the private company ABIVAX and is currently undergoing phase II clinical trials (ulcerative colitis, rheumatoid arthritis). In collaboration with the CNRS, it has been observed that drug ABX is a potent anti-inflammatory drug able to specifically induce the overexpression of the miR-124, described for its anti-inflammatory properties. The aim of my PhD project was to characterize in vitro the phenotypic modulations and molecular mechanisms involved by drug ABX, on Human Monocyte-Derived Macrophages (Hu MDM) of healthy donors in an inflammatory context, and pretreated with drug ABX versus control. The data obtained on six Hu MDM show on the one hand, a significant decrease in the membrane receptors of the M1 phenotype (CD86, CD274) and on the other hand, a significant decrease in the factors involved in the TLR4 signaling pathway (p65/RelA, IkBζ/NFKBIZ, TRAF6). In addition, the secretory profile shows a significant decrease of a set of pro-inflammatory proteins such as cytokines (IL-6, TNFα, IL-1β), proteins involved in cell adhesion and leukocyte recruitment (ICAM-1, CXCL1), as well as the chemokine responsible for the infiltration of macrophages (MCP-1/ CCL2). Remarkably, the data obtained with 14 Hu MDM, show a significant overexpression of micro-RNA 124 of 3.4 times that of the DMSO control. All of these data suggest that drug ABX limits excessive inflammation and could play a role in the control of cellular homeostasis. The overexpression of miR-124 is consistent with in vitro data obtained with T CD4 lymphocyte and human PBMC data, as well as clinical data from ulcerative colitis patients. For the first time, the laboratory identifies the immunomodulatory potential of drug ABX in inflammation. By inducing specific overexpression of miR-124, drug ABX attenuates the pro-inflammatory profile of macrophages by a negative feedback loop of the TLR4/NF-kB signaling. MiR-124 potentiates the homeostatic effect of drug ABX. This new chemical molecule ABX could represent a new therapeutic perspective, in order to rebalance some mediators involved in innate and adaptive immunity.