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Les protéases et leurs inhibiteurs sécrétés par la cellule épithéliale : acteurs de l'inflammation et de la douleur

Abstract : Proteases are involved in some biologic processes and their origins are variable (immune cells, epithelial cells...). Their activity is regulated by antiproteases. This study investigates the balance between proteases and their inhibitors in pathologies which modify epithelium integrity. Consequences of an unbalance in proteolytic activity was studied in two chronic pathologies with different components: Inflammatory Bowel Disease (IBD) (cycles of inflammatory boost) and Irritable Bowel Syndrome (IBS) (cycles of pain symptoms). Colonic mucosa from IBS patients releases trypsin activity. The origin and the functions of this activity are not well defined. This study investigated the source of this trypsin activity in the côlon of IBS patients, its nature and its role in neuronal activation. Trypsin activity from IBS patients is increased mostly in epithelial cells. Stimulation of epithelial cell monolayers with LPS or epinephrine induces an increase of trypsin-3 quantity and its secretion specifically in the basal side of epithelial cells. This is in correlation with the increase of trypsin activity. Trypsin-3 hyperactivity at the basal side provokes a loss of epithelium barrier function, which is also found in colons of IBS patients. Then, we have highlighted that trypsin-3 is able to activate human myenteric neurons and murine sensitive neurons. In vivo, its intra-rectal administration to mice induces a visceral hypersensitivity dependent of PAR2 (Protease Activated Receptors 2). Thus, intestinal epithelial cells from IBS patients produce and release trypsin-3 specifically on their basal side. This trypsin activity activates sensitive neurons which participate to visceral hypersensitivity, a major symptom of IBS patients. Inflammatory pathologies could be a source of proteolytic malfunction. IBD patients have a dysregulation of elastolytic balance in the colon. Our team has shown that ELAFIN (an elastase inhibitor) delivered by the bacteria genetically modified L.lactis near the inflamed mucosa, protects mice from intestinal inflammation. However, the protective mechanisms induced by ELAFIN need to be investigate. ELAFIN is an elastase inhibitor but have also antimicrobial properties. With the aim to highlight what function of ELAFIN owns anti-inflammatory properties, mutants of ELAFIN have been generated and were insered into L.lactis: a first mutant lacked its antiprotease function, a second lacked antimicrobial properties and a last mutant lacked both properties. In intestinal epithelial monolayers, ELAFIN delivered by L.lactis protects against inflammation: a restauration of epithelial barrier function and a decrease of pro-inflammatory cytokines (CXCL8 and IP10) are observed. Mutation of antimicrobial domain doesn't affected these properties. Nevertheless, the absence of inhibitory loop annihilates anti-inflammatory functions of ELAFIN. This work highlights the importance of proteolytic balance inside the epithelial cell in intestinal pathologies. The balance between proteases and antiproteases plays an important role in epithelial homeostasis.
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Claire Rolland-Fourcade. Les protéases et leurs inhibiteurs sécrétés par la cellule épithéliale : acteurs de l'inflammation et de la douleur. Physiologie [q-bio.TO]. Université Paul Sabatier - Toulouse III, 2017. Français. ⟨NNT : 2017TOU30353⟩. ⟨tel-02004310⟩

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