Impact of therapeutic α4β7 integrin inhibition on in vivo monocyte homing and intestinal wound healing in inflammatory bowel diseases

• Applicant: Professor Dr. Sebastian Zundler
• Subject Area: Gastroenterology
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 411013818

Inhibition of lymphocyte gut homing with antibodies to α4β7 integrin is a novel mainstay in the therapy of inflammatory bowel diseases (IBD). However, mechanistic investigations have so far focused on lymphocytes and ignored a potential impact on monocyte homing, although monocytes and macrophages as their descendants play a crucial role in the pathogenesis of IBD. Moreover, macrophages are essential for wound healing, which is important in IBD both to bridge disease-inherent mucosal defects and to close wounds arising from disease-associated surgery. Our preliminary data show that α4β7 is differentially expressed on human monocytes with a predominant expression in non-classical monocytes, which preferentially develop to M2-like macrophages. Moreover, we could show that α4β7 is functionally relevant since dynamic adhesion of human monocytes to the addressin MAdCAM-1 is inhibited by the clinically used anti-α4β7 antibody vedolizumab.In the light of a recent report suggesting that wound healing after surgery is impaired in vedolizumab-treated patients, this leads us to postulate that anti-α4β7 treatment impairs homing of non-classical monocytes leading to reduced intestinal numbers of M2-like macrophages and reduced promotion of tissue regeneration. Indeed, preliminary experiments in mice showed that anti-α4β7 treatment inhibited both non-classical monocyte homing and intestinal wound healing in vivo going along with a lower level of M2-like macrophages. Thus, the central hypothesis of this project is that specific monocyte subsets use different gut homing pathways and that these monocyte subsets develop into different intestinal macrophage subsets with different contribution to homeostasis, inflammation and wound healing. Therefore, the aim of this project is to investigate integrin-dependent monocyte gut homing and its functional consequences in detail. To this end we will characterize integrin expression profiles on murine peripheral blood monocytes and intestinal macrophages in steady-state and DSS colitis. Furthermore, we will study the regulation of integrin expression and macrophage differentiation in vitro. We will also analyze the relevance of the monocyte integrins in functional in vitro assays and in an in vivo model of gut homing including intravital microscopy. To assess intestinal wound healing we will make use of an in vivo intestinal wound healing model and evaluate the role of α4β7-mediated monocyte homing and M2-like macrophages. Finally, in a translational approach, we will study shifts in monocyte and macrophage populations in vedolizumab-treated patients and assess the impact of human macrophages on intestinal wound healing in co-culture models. Taken together, this project will help to further shape our pathogenetic concepts of IBD and might lead to the identification of potential future targets for therapy as well as the elucidation of the mechanisms of action and clinical consequences of existing anti-adhesion therapies.

• DFG Programme: Research Grants