Team Anne TSICOPOULOS

Pulmonary Immunity

Among respiratory diseases, allergic asthma and pulmonary infections represent major problems of public health. These diseases affect millions of people, are in constant increase and are a major cause of morbidity and mortality. Although considerable therapeutic progress has been made over the last 20 years, there is still no treatment able to modify the natural course of chronic respiratory diseases. These diseases share common key target cells involved in their pathogenesis: the endothelial cells (EC) as a barrier allowing the recruitment of inflammatory cells in the tissues, and the lymphoïd cells, as major actors of the immune response to environmental challenges. Our goal is to evaluate how these cells and their mediators can orchestrate the host inflammatory reaction and tissue remodeling in response to allergens, bacteria or stress and to characterize some of the mechanisms involved in the immune response associated with these respiratory diseases in order to highlight potential therapeutic strategies.

The project will focus on the mechanisms involved in the regulation of pulmonary immunity by endothelial cells in sepsis and by lymphoid cells in asthma with a new focus on the recently described innate lymphoid cells (ILC).

 

Theme 1: Endothelial cells (EC)

1.1 Proteoglycan endocan in sepsis (P Lassalle, CR1, D Mathieu, PU-PH, N de Freitas Caires, CRI, A Scherpereel, PU-PH, H Yassine PhD, E Parmentier, PH)

In the context of endothelial cells in sepsis, we will evaluate the potential protective role of endocan in sepsis. Our hypothesis is that in severe sepsis involving intravascular neutrophil activation, endocan proteolysis may occur, through neutrophil-derived cathepsin G, leading to the generation of endocan fragments able to exacerbate inflammation by competitive inhibition with full length endocan. The project will thus focus on deciphering the role of endocan, its glycan, and its proteolytic fragments in the pathophysiology of sepsis, in vitro and in vivo in particular in cohorts of septic patients with acute lung injury in Lille CHRU Intensive Care Unit.

1.2 IL-33 in asthma and sepsis (C Glineur, CR1, A Scherpereel, PU PH, C Duez, CR1, P de Nadai, MCF, A Tsicopoulos, DR2, P Lassalle, CR1)

A predominant role of IL-33 has been shown in asthma, through its pro Th2 activity, and in sepsis through neutrophil recruitment. IL-33 is both a cytokine, and a chromatin-associated transcriptional regulator in EC. The molecular mechanisms that drive expression of IL-33 in EC are unknown and will be deciphered in this project. In particular post-translational modifications and transcription factors modulating IL-33 expression will be identified. The role of IL-33 in the interactions between primary endothelial cells and lymphoid cells in asthma, and neutrophils in sepsis will be evaluated, in particular by using genetically modified mice.

 

Theme 2: Lymphoid cells

The second theme will focus on lymphoid cells including adaptive classical T helper subsets and innate lymphoid cells (ILC) including NK cells. 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 poorly understood. In this part, we will focus on two major determinants of severe asthma, aero contaminants including pollutants and infections, and obesity.

4.2.1. Aero contaminants  (C Duez CR1, T Perez PH, P de Nadai MCF, N Just PH, S Fry PH, Y Fan PhD, A Tsicopoulos DR2, S Ait Yahia post doc, P Marquillies TR, P Ramon PH, A Prevotat PH, C Fournier PH)

Recent studies have highlighted the multiplicity of asthma phenotypes, each corresponding to different pathophysiological mechanisms. Therefore our new strategy will be to focus on some phenotypes of severe asthma that resist to current treatments. These severe phenotypes exhibit, beside the Th2 type profile an additional Th17/Th22 type profile. Pollutants incuding Aryl hydrocarbon receptor (AhR) ligands, as well as infections are major environmental exacerbation factors in severe asthma. The aim of this project will be to evaluate if AhR ligands or Pattern Recognition Receptor (PRR) ligands in conjunction with allergens can participate in the activation of Th17/Th22 and/or ILC, subsets potentially involved in the severity of asthma. The effects will be evaluated in vitro on cells obtained from asthmatics or controls, and in in vivo chronic models of house dust mite-induced asthma using genetically modified animals.

4.2.2 Obesity (A Tsicopoulos DR2, B Wallaert PU PH, L Everaere PhD, C Glineur CR1, Han Vorng IE)

A recently described risk factor of asthma is obesity. Obesity- triggered asthma exhibits a severe phenotype with pulmonary neutrophils and a mixed Th2/Th17 profile. IL-33 is produced by adipocytes and triggers activation of lymphoid cells. Thus, this project aims to test experimentally the hypothesis that alterations in metabolic dysfunction can favour the development or exacerbate asthma (Collaboration D Dombrowicz, U1011).

 

Altogether, this project should identify novel therapeutic strategies in inflammatory diseases of the lung including asthma and sepsis.

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