Theme 1: Endothelial cells
The first theme focuses on endothelial cells, a major cell type allowing in response to local injury, the transmigration and fine tuning of inflammatory cells into tissues.
1.1. Endocan in sepsis and acute lung injury
(P Lassalle CR1, D Mathieu PU-PH, N de Freitas Caires PhD, A Gaudet PhD, M Hureau MD, E Parmentier PH)
Pulmonary endothelial cells play a major role in sepsis-mediated acute lung injury, allowing a massive transmigration of inflammatory cells into the lung tissue. In this context, we evaluate the potential protective role of endocan, a lung endothelial specific proteoglycan able to inhibit leukocyte transmigration acroos endothelial cells. Our hypothesis is that in severe sepsis, endocan can regulate the lung inflammatory reaction. In particular endocan proteolysis can occur, through neutrophil-derived cathepsin G, leading to the generation of endocan fragments able to exacerbate inflammation by competitive inhibition with full length endocan. Thus, the project focuses on deciphering the role of endocan and its major proteolytic fragments in the pathophysiology of acute lung injury, in vitro and in vivo in mouse models of sepsis/acute lung injury as well as in cohorts of septic patients at high risk of acute lung injury followed in the Intensive Care Unit of the CHRU of Lille.
1.2. Endocan in asthma
(P de Nadai MCF, P Lassalle CR1, De Freitas caires N PhD, A Prevotat PH, F Wallyn PH, Chenivesse C PU PH, J Balsamelli TR)
Some forms of severe asthma are characterized by an important infiltration of neutrophils in induced sputum and in bronchoalveolar lavages. Given the anti inflammatory properties of Endocan, the project will evaluate if endocan can modulate in particular neutrophil infiltration in chronic mouse models of house dust mite induced allergic inflammation. The role of endocan will be evaluated by using endocan deficient mice. Special attention will be paid to the effect on bronchial remodelling in this model as well as on the role of clived fragments of endocan.
Theme 2: Lymphoid cells
The second theme focuses on lymphoid cells including adaptive classical T helper subsets and innate lymphoid cells (ILC). ILC do not express antigen receptors but express the same cytokines and transcription factors than their T helper adaptive counterparts. The function of ILC in the development and exacerbation of asthma is still poorly understood. In this part, we focus on three major determinants of severe asthma including pollutants, microorganisms, and metabolism.
(P de Nadai MCF, B Wallaert PU PH, N Just PH, J Balsamelli TR, J Carrard PhD)
Asthma is a disease strongly influenced by the environment. Pollutants, such as polycyclic aromatic hydrocarbons (PAHs), are suspected to enhance the severity of asthma. These severe asthma phenotypes are characterized by high doses of corticosteroid treatment and sometimes resistance to it and are associated with bronchial remodeling. In these patients, a Th17/Th22 response develops in addition to a Th2 profile. Th17/Th22 cells express the Aryl hydrocarbon Receptor (AhR), a PAHs-binding transcription factor, which could be a link between pollutants and severe asthma. The project aims to evaluate, the role of AhR-binding molecules in the activation of Th17/Th22 and ILC, populations potentially implicated in the severity of asthma in a model of polluted nanoparticles which have the particularity of going very deeply into the lung. The effects will be evaluated in vitro on cells obtained from asthmatic subjects or controls, and in vivo, in models of asthma induced by chronic exposure to house dust mite. Mechanisms involved will be deciphered using genetically modified animals.
2.2.Microorganisms and innate immunity
(C Chenivesse PU PH,A Tsicopoulos DR2, M Bouté PhD, T Perez PH, S Fry PH, S Ait Yahia IE, C Audousset, PhD, Alvarez-Simon D, PhD)
Exposure to microorganisms has a dual role in asthma. On one hand it can be protective in particular in the early stages of life, but on the other hand it also acts as a major environmental exacerbation factor in severe asthma. The project evaluates the role of Pattern Recognition Receptor (PRR) ligands in conjunction with allergens on asthma. In particular, the role of NOD1 and NOD2 will be evaluated in both HDM-induced asthma and in a severe chronic neutrophilic model of asthma, as well as the participation of innate lymphoid cells. These studies are performed both in cohorts of severe asthma patients and in animal models of asthma taking advantages of genetically modified animals.
2.3. Metabolism and lymphoid cells
(A Tsicopoulos DR, Chenivesse C PU PH, Ait Yahia Saliha IE, Fournier C PH, Wemeau L PH)
We have previously shown that obesity exacerbates house dust mite induced asthma through the upregulation of ILC and Thelper populations in the lung. Obesity as well as asthma are known to be show circadian variations, but almost no studies have evaluated the underlying molecular mechanisms. We will analyze if allergen-induced asthma is associated with circadian variations of lymphoid cells, and if these variations may impact the severity of asthma, in particular associated with obesity.
Altogether, this project should identify novel therapeutic strategies in inflammatory diseases of the lung including asthma and sepsis.