Focus on the early step of atherosclerosis: synergetic effect of S100A8/A9 and IL-17D

Cardiovascular diseases (CVD) are the leading cause of deaths in Europe. Most of CVD are the consequence of the degradation of atherosclerotic lesions. The early event in atherosclerotic development is the attraction, recruitment and adhesion of monocytes by endothelial cells, a multistep process involving many different signal molecules, including cytokines.

The overall objective of this project is to evaluate the crosstalk between S100A8/A9, two Ca²⁺ -binding proteins and IL-17D signalling as a central molecular process towards atherosclerosis.

University of Luxembourg project, PI: Eric Tschirhart, 2013 – 2017

Regulation of Ca²⁺ -dependent NADPH oxidase activation in neutrophils: A modelling-based approach of S100A8/A9-dependent intracellular signaling pathways,

Neutrophils play a fundamental role in innate immunity by neutralizing pathogens through NADPH oxidase-produced reactive oxygen species. Over-activation of neutrophils can cause tissue damage leading to the development of chronic inflammatory diseases (arthritis, atherosclerosis, cancer...).

This project aims to characterize the complex regulatory network underlying NADPH oxidase activation by an interdisciplinary approach coupling the methodologies of computational biology with functional physiological assays. Especially, we will focus our research on Ca²⁺ /phosphorylation dependent-signalling cascades and their relationship with the spatiotemporal control of S100A8/A9-mediated NADPH oxidase activation.

University of Luxembourg project, PI: Sabrina Brechard, 2016-2018

Role of neutrophils in rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases (prevalence of about 1% worldwide) leading to progressive joint destruction and deformation. Currently, no treatment is sufficient to reverse tissue injury in RA patients. The etiology of RA remains unknown but various inflammatory mechanisms have been shown to be involved, especially reactive oxygen species produced by neutrophils present at inflammation sites. Although these cells are the most abundant cells in synovial fluid of RA patients and have been predominantly associated to RA pathogenesis, their role in RA development has been the subject of less intensive research than other infiltrated cells.

In this project, we will determine the status of neutrophils from synovial fluid of patients with RA in terms of mRNA and miRNA expression profiles, as well as chromatin and epigenetic mechanisms. The impact of S100A8/A9 proteins on these genomic and epigenetic analysis will be investigated.

Intracellular and extracellular role of S100A8/A9 in neutrophil pro-inflammatory functions

Neutrophils are the first cells to reach the site of inflammation and the most powerful killers of invading pathogens. To fulfill this function, they are able to deploy a sophisticated arsenal of cytotoxic substances (e.g.proteases, reactive oxygen species) as well as secrete an impressive array of cytokines and chemokines to recruit other immune cells. Over liberation of such molecules can lead to cellular and molecular damages causing the perpetuation of inflammation and consequently chronic inflammatory diseases.

Our objective in this project is to characterize the mechanisms involved in the regulation of cytokine secretion and degranulation by neutrophils. An emphasis will be placed on the role of intracellular and extracellular S100A8/A9, which represent 40% of cytosolic proteins in neutrophils and are well known to have multiple functionalities through their properties of damage-associated molecular pattern molecules.