Escape of HIV-1-Infected Dendritic Cells from TRAIL-Mediated NK Cell Cytotoxicity during NK-DC Cross-Talk—A Pivotal Role of HMGB1

Early stages of Human Immunodeficiency Virus-1 (HIV-1) infection are associated with local recruitment and activation of important effectors of innate immunity, i.e. natural killer (NK) cells and dendritic cells (DCs). Immature DCs (iDCs) capture HIV-1 through specific receptors and can disseminate the infection to lymphoid tissues following their migration, which is associated to a maturation process. This process is dependent on NK cells, whose role is to keep in check the quality and the quantity of DCs undergoing maturation. If DC maturation is inappropriate, NK cells will kill them (“editing process”) at sites of tissue inflammation, thus optimizing the adaptive immunity. In the context of a viral infection, NK-dependent killing of infected-DCs is a crucial event required for early elimination of infected target cells. Here, we report that NK-mediated editing of iDCs is impaired if DCs are infected with HIV-1. We first addressed the question of the mechanisms involved in iDC editing, and we show that cognate NK-iDC interaction triggers apoptosis via the TNF-related apoptosis-inducing ligand (TRAIL)-Death Receptor 4 (DR4) pathway and not via the perforin pathway. Nevertheless, once infected with HIV-1, DCHIV become resistant to NK-induced TRAIL-mediated apoptosis. This resistance occurs despite normal amounts of TRAIL released by NK cells and comparable DR4 expression on DCHIV. The escape of DCHIV from NK killing is due to the upregulation of two anti-apoptotic molecules, the cellular-Flice like inhibitory protein (c-FLIP) and the cellular inhibitor of apoptosis 2 (c-IAP2), induced by NK-DCHIV cognate interaction. High-mobility group box 1 (HMGB1), an alarmin and a key mediator of NK-DC cross-talk, was found to play a pivotal role in NK-dependent upregulation of c-FLIP and c-IAP2 in DCHIV. Finally, we demonstrate that restoration of DCHIV susceptibility to NK-induced TRAIL killing can be obtained either by silencing c-FLIP and c-IAP2 by specific siRNA, or by inhibiting HMGB1 with blocking antibodies or glycyrrhizin, arguing for a key role of HMGB1 in TRAIL resistance and DCHIV survival. These findings provide evidence for a new strategy developed by HIV to escape immune attack, they challenge the question of the involvement of HMGB1 in the establishment of viral reservoirs in DCs, and they identify potential therapeutic targets to eliminate infected DCs

4D cardiac imaging at clinical 3.0T provides accurate assessment of murine myocardial function and viability

We validate a 4D strategy tailored for 3T clinical systems to simultaneously quantify function and infarct size in wild type mice after ischemia/reperfusion, with improved spatial and temporal resolution by comparison to previous published protocols using clinical field MRI systems

Babette : Accès à une alimentation de qualité pour tous - Systèmes alimentaires inclusifs et outils de formation

Guide pratique.International audienceCe guide traite de l’accès à une alimentation dequalité pour tous selon deux angles complémentaires.Tout d’abord celui de la mise en placede systèmes alimentaires courts, inclusifs et durables à destination des personnes en situationéconomique difficile : modèle économique etorganisation logistique, gouvernance et animation. Ensuite, nous abordons l’accompagnementet la formation des personnes et des familles àune alimentation plus durable : objectifs,thèmeset démarches de formation ou de sensibilisation.Le guide s’appuie sur des exemples et mobilise également quelques notions plus générales comme celles de système alimentaire etde posture pédagogique. Nous donnons aussi une large place aux recommandations etaux conseils pratiques. Ceux-ci sont à prendrecomme des repères sur lesquels s’appuyer pourraisonner ses propres choix et les adapter à unesituation qui est toujours spécifique. Exemples,notions générales et recommandations se complètent

Babette : Accès à une alimentation de qualité pour tous - Systèmes alimentaires inclusifs et outils de formation

Guide pratique.International audienceCe guide traite de l’accès à une alimentation de qualité pour tous selon deux angles complémentaires.Tout d’abord celui de la mise en place de systèmes alimentaires courts, inclusifs et durables à destination des personnes en situationéconomique difficile : modèle économique et organisation logistique, gouvernance et animation. Ensuite, nous abordons l’accompagnement et la formation des personnes et des familles à une alimentation plus durable : objectifs,thèmeset démarches de formation ou de sensibilisation.Le guide s’appuie sur des exemples et mobilise également quelques notions plus générales comme celles de système alimentaire et de posture pédagogique. Nous donnons aussi une large place aux recommandations et aux conseils pratiques. Ceux-ci sont à prendre comme des repères sur lesquels s’appuyer pour raisonner ses propres choix et les adapter à une situation qui est toujours spécifique. Exemples, notions générales et recommandations se complètent

VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation

Abstract Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome