Team Inserm 2: "Proteolytic Mechanisms in Inflammation"
Leader : G. Lalmanach

Team 2 is associated (primary field) to the ITMO (Thematic Institute Multi Organisms) « Pathophysiology, Metabolism, Nutrition ». Secondary thematic field: ITMO "Molecular and structural bases of living organisms".

Our work is structured around two major axes: 1) Proteolytic mechanisms associated with two chronic pulmonary pathologies (Chronic Obstructive Pulmonary Disease Broncho, COPD and Fibrosis) and 2) "Targeting, control and regulation of proteolytic activity".

Axis 1: Due to the variety of cellular and molecular processes they impact, proteases are a promising candidate for therapeutic targets. However, their implications in some key processes of chronic lung disease (COPD, Fibrosis) are far from being understood. Our project is interested in two families of proteases (tissue kallicreins, KLKs and cysteine cathepsins, CPs) that have not been studied or only rarely in these diseases. Our work focuses on the role(s) of KLKs in remodeling the alveolar-capillary barrier and airway epithelium that accompany emphysema and chronic bronchitis in COPD (stable and exacerbated) as well as the interactions between the KLKs system and the innate immune response. Studies on CPs focus on the mechanisms for controlling the integrity of the epithelial barrier in relation to intercellular junctions, and their involvement in fibrotic mechanisms.

Axis 2: Work of this axis focuses on two types of proteases: lysosomal cysteine cathepsins (CPs) and neutrophil serine proteases (NSPs), which are respectively more particularly involved in diseases with fibrotic components (pulmonary fibrosis) and inflammatory diseases with a dominant neutrophilic component (COPD). Various molecular tools (probes, inhibitors, neutralizing antibodies) are being developed to better understand the physiopathological consequences of modulating the activity of these proteases, the ultimate objective being to evaluate the relevance of developing therapeutic intervention strategies. To do this, each project is based on in vitro studies on the modalities of action of molecules of interest and on studies using appropriate physiopathological models (mouse animal and non-human primate models, rare human pathologies).