Overview
Several pathological and physiopathological contexts, such as sepsis, organ transplantation and some cancers, are associated with the development of organ failures. These dysfonctions result from complex interactions between inflammation, immune activation and microcirculatory disorders, particularly involving the endothelium and immune system cells.
Previous studies have shown that inflammation is a key mechanism in the development of microvascular dysfunction. Whether sterile or infectious, the inflammatory response is characterized by an initial acute phase that, upon resolution, progresses toward the gradual development of chronic organ dysfunction and, ultimately, complications or acute events.
In organ transplantation, initial ischemia-reperfusion induces acute sterile inflammation, activating endothelial cells, neutrophils and specific tissue cells, such as pancreatic β-cells within islets of Langerhans or type II alveolar epithelial cells in the lung. Furthermore, in pancreatic islet transplantation, the ischemia-reperfusion associated with graft transport and preparation is compounded by an acute inflammatory reaction due to the infusion of islets into the bloodstream of the portal vein (Instant Blood-Mediated Inflammatory Reaction – IBMIR). This step leads to significant loss of transplanted islets and, ultimately, function loss of the graft in the following months.
Similarly, in gastric cancer, tumor development is paired with a sterile pro-inflammatory modification of the tumor tissue, associated with an increased thrombogenic risk.
In the context of non-sterile inflammation, septic shock is characterized by a state of hyper-inflammation in response to a pathogen, leading to intense cellular activation — particularly of leukocytes, endothelium and platelets. This physiological state induces an excessive and dysregulated coagulation activation (immunothrombosis), leading to disseminated intravascular coagulation (DIC) in 30% of cases. Our work has highlighted the role of neutrophil extracellular traps (NETs) in the dysregulation of immunothrombosis and the development of DIC. We have also identified a fibrinolysis defect during sepsis and potential therapeutic targets.
We have previously demonstrated that the secretome — in particular extracellular vesicles (EVs) represented by microvesicles (MVs) and exosomes — play a pivotal role in the pathogenesis of vascular and organ dysfunctions. Indeed, EVs serve as both relevant pathogenic markers of cellular activation and biological effectors involved in intercellular communication and propagation of the inflammatory response. We have identified several physiopathological situations associated with the plasma release of EVs. These autocrine and paracrine mediators were demonstrated to have pro-senescent, pro-inflammatory and pro-coagulant effects and be responsible for endothelial damage (in rats and mice) or tissue injury (spleen, vessels or pancreatic islets).
The relevance of EVs as pathogenic markers of tissue damage, as well as their utility for therapeutic monitoring, have been confirmed in clinical cohorts of diabetic patients undergoing islet transplantation; their role in hypercoagulability has also been demonstrated in septic patients.
In conclusion, we have shown that cytokine-mediated endothelial and tissue damages are, at least in part, amplified by deleterious EVs during both sterile (transplantation) and non-sterile (infection) immunothrombosis. Conversely, the therapeutic potential of repurposed or reprogrammed EVs is currently under investigation.
Organization of Group 2
The research program of our group builds on the expertise of its members and complementary approaches addressing three specific physiopathological situations: