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.
- Gaudet et al. Cleaved endocan acts as a biologic competitor of endocan in the control of ICAM-1-dependent leukocyte diapedesis. J Leukoc Biol. 2020 ; 107:833.
- Gaudet et al. Endocan regulates acute lung inflammation through control of leukocyte diapedesis. J Appl Physiol. 2019;127(3):668.
- De Freitas Caires et al. Endocan, sepsis, pneumonia, and acute respiratory distress syndrome. Crit Care. 2018 Oct 26;22(1):280
- De Freitas caires et al. Highlight on mouse endocan. Circ Res. 2015;116(8):e69-70
- De Freitas Caires et al. Identification of a 14 kDa endocan fragment generated by cathepsin G, a novel circulating biomarker in patients with sepsis. J Pharm Biomed Anal. 2013 May 5;78-79:45.
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.
- Poulain-Godefroy et al. The Aryl Hydrocarbon Receptor in Asthma: Friend or Foe? Int J Mol Sci. 2020;21(22):8797.
- Tsicopoulos et al. Role of CCL18 in asthma and lung immunity. Clin Exp Allergy. 2013;43(7):716.
- Chang Y et al. The chemokine CCL18 generates adaptive regulatory T cells from memory CD4+ T cells of healthy but not allergic subjects. FASEB J. 2010;24(12):5063
- de Nadai et al. CCR5 usage by CCL5 induces a selective leukocyte recruitment in human skin xenografts in vivo. J Invest Dermatol. 2006;126(9):2057
- de Nadai et al. Involvement of CCL18 in allergic asthma. J Immunol. 2006;176(10):6286
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.
- Carrard et al. Chronic exposure to benzo(a)pyrene-coupled nanoparticles worsens inflammation in a mite-induced asthma mouse model. Allergy. 2020 Oct 9. doi: 10.1111/all.14619. Epub ahead of print
- Farah et al. Extractable lipids from Phleum pratense pollen grains and their modifications by ozone exposure. Aerobiologia, Springer Verlag, 2020 ; 36:171.
- Plé et al. Polycyclic aromatic hydrocarbons reciprocally regulate IL-22 and IL-17 cytokines in peripheral blood mononuclear cells from both healthy and asthmatic subjects. PLoS One. 2015;10(4):e0122372
- Chassard et al. Kinetic of NO2 uptake by Phleum pratense pollen: chemical and allergenic implications. Environ Pollut. 2015;196:107
- Tsicopoulos et al. Environmental and genetic contribution in airway epithelial barrier in asthma pathogenesis. Curr Opin Allergy Clin Immunol. 2013;13(5):495
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.
- Bouté et al. Direct activation of the aryl hydrocarbon receptor by dog allergen participates in airway neutrophilic inflammation. Allergy. 2021, in press
- Devulder et al. Aberrant anti-viral response of natural killer cells in severe asthma. Eur Respir J. 2020;55(5):1802422
- Grosbois et al. Long-term effect of home-based pulmonary rehabilitation in severe asthma. Respir Med. 2019;157:36
- Ait Yahia et al. CCL17 production by dendritic cells is required for NOD1-mediated exacerbation of allergic asthma. Am J Respir Crit Care Med. 2014;189(8):899
- Chenivesse et al. Pulmonary CCL18 recruits human regulatory T cells. J Immunol. 2012;189(1):128
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.
- Ait Yahia et al. NOD1 sensing of house dust mite-derived microbiota promotes allergic experimental asthma. J Allergy Clin Immunol, 2021, in press.
- Everaere et al. Innate lymphoid cells at the interface between obesity and asthma. Immunology. 2018;153(1):21
- Everaere et al. Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity. J Allergy Clin Immunol. 2016;138(5):1309
- Awad et al. Natural killer cells induce eosinophil activation and apoptosis. PLoS One. 2014;9(4):e94492.
- Azzaoui et al. CCL18 differentiates dendritic cells in tolerogenic cells able to prime regulatory T cells in healthy subjects. Blood. 2011;118(13):3549
Altogether, this project should identify novel therapeutic strategies in inflammatory diseases of the lung including asthma and sepsis.