Crohn’s disease and ulcerative colitis are severe inflammatory bowel diseases (IBD) that can end up in ulcer and fibrosis of the intestine. They are a worldwide health-care problem with a continuously increasing incidence. The available therapies are not curative, at best they provide temporary symptomatic relief but a large proportion of patients fail to respond or achieve remission in the short or the long term. Thus, there is a real need to develop new drugs less toxic and able to act both on the acute and chronic phases of the disease. IBD, whose etiology is still unknown, are characterized by an impaired and/or inappropriate pro-inflammatory response toward intestinal bacteria involving the recruitment of inflammatory macrophages, neutrophils and lymphocytes Th1/Th17, which induce the production of pro-inflammatory cytokines (i.e. TNFa, IL-23, IL-17) and an oxidative stress, both involved in the development of intestinal damage. Among different environmental factors, stress, via the secretion of catecholamines, has been shown to activate catecholaminergic receptors. a-adrenoceptors subtypes are described to boost inflammation while ß2-adrenergic signaling suppresses both innate and adaptive immunity. A third subtype, less studied, within this family is the ß-3 isoform of adrenergic receptor (ß3-AR). Knowledge concerning the relationship between ß3-AR and immunity is sparse. Nevertheless, we have recently demonstrated that the ß3-AR is expressed and functional in human macrophages. Its stimulation leads to anti-inflammatory and antioxidant responses and induces polarization toward a M2-like phenotype. Moreover, we have demonstrated that ß3-AR is also expressed on human lymphocytes and that its stimulation leads to cAMP production, a second messenger implicated in the suppressive activity of Tregs toward lymphocytes and dendritic cells. Lastly, our preliminary results in vivo show that a weekly exposure to a ß3-agonist results in protection against polyp formation in ApcMin mice, via an anti-inflammatory effect. Altogether, these results indicate that ß3-adrenoceptor stimulation could be of interest in inflammatory bowel diseases. However, ß3-agonists are highly lipophilic. Therefore, we intend to use our recently patented technology that uses lipoproteins (HDL-derivatives) as nanovectors both to solve solubility problems and to improve drug targeting to immune cells. Specific aims: 1) To dissect the role of ß3-AR on the host cell immune response using human in vitro, ex vivo explants and murine in vivo models, in order to bring a “proof of concept". 2) to develop a cost effective ß3-agonist formulation based on lipoprotein that could be given to patients in view to maintaining remission of inflammatory bowel diseases’ patients. To achieve these objectives, we propose a multidisciplinary approach associating expertise in human primary cell culture, human explants (organotypic cultures), in vivo studies in rodent IBD models, pharmacokinetics and pharmaco-imagery techniques. In terms of societal impact, we expect to develop a new formulation with a ß3-agonist that will be tested in clinical trials for its ability to maintain remission and prevent relapse in patients with IBD. The economic impact of this new formulation appears very promising considering the frequency of IBD worldwide and the need for more efficient and/or less toxic treatments. An originality of our approach worth to mention is that we want to re-educate immune cells instead of depleting them, like with recombinant antibodies therapy, thus potentially allowing the chronic use of the ß3-agonist formulation. B3ID is a translational research project that will provide a young researcher the opportunity to develop a research thematic and to constitute its own research group.