Disrupting the EMMPRIN (CD147)-cyclophilin A interaction reduces infarct size and preserves systolic function after myocardial ischemia and reperfusion.

Objective-Inflammation and proteolysis crucially contribute to myocardial ischemia and reperfusion injury. The extracellular matrix metalloproteinase inducer EMMPRIN (CD147) and its ligand cyclophilin A (CyPA) may be involved in both processes. The aim of the study was to characterize the role of the CD147 and CyPA interplay in myocardial ischemia/reperfusion (I/R) injury.Methods and Results-Immunohistochemistry showed enhanced expression of CD147 and CyPA in myocardial sections from human autopsies of patients who had died from acute myocardial infarction and from mice at 24 hours after I/R. At 24 hours and 7 days after I/R, the infarct size was reduced in CD147(+/-) mice vs CD147(+/+) mice (C57Bl/6), in mice (C57Bl/6) treated with monoclonal antibody anti-CD147 vs control monoclonal antibody, and in CyPA(-/-) mice vs CyPA(+/+) mice (129S6/SvEv), all of which are associated with reduced monocyte and neutrophil recruitment at 24 hours and with a preserved systolic function at 7 days. The combination of CyPA(-/-) mice with anti-CD147 treatment did not yield further protection compared with either inhibition strategy alone. In vitro, treatment with CyPA induced monocyte chemotaxis in a CD147-and phosphatidylinositol 3-kinase-dependent manner and induced monocyte rolling and adhesion to endothelium (human umbilical vein endothelial cells) under flow in a CD147-dependent manner.Conclusion-CD147 and its ligand CyPA are inflammatory mediators after myocardial ischemia and reperfusion and represent potential targets to prevent myocardial I/R injury.

The neutrophil NLRC4 inflammasome selectively promotes IL-1β maturation without pyroptosis during acute Salmonella challenge.

The macrophage NLRC4 inflammasome drives potent innate immune responses against Salmonella by eliciting caspase-1-dependent proinflammatory cytokine production (e.g., interleukin-1β [IL-1β]) and pyroptotic cell death. However, the potential contribution of other cell types to inflammasome-mediated host defense against Salmonella was unclear. Here, we demonstrate that neutrophils, typically viewed as cellular targets of IL-1β, themselves activate the NLRC4 inflammasome during acute Salmonella infection and are a major cell compartment for IL-1β production during acute peritoneal challenge in vivo. Importantly, unlike macrophages, neutrophils do not undergo pyroptosis upon NLRC4 inflammasome activation. The resistance of neutrophils to pyroptotic death is unique among inflammasome-signaling cells so far described and allows neutrophils to sustain IL-1β production at a site of infection without compromising the crucial inflammasome-independent antimicrobial effector functions that would be lost if neutrophils rapidly lysed upon caspase-1 activation. Inflammasome pathway modification in neutrophils thus maximizes host proinflammatory and antimicrobial responses during pathogen challenge.

Netting neutrophils in skin wounds recruit and activate plasmacytoid dentritic cells

Les mécanismes qui régulent le processus de guérison de la peau lésée ne sont pas entièrement compris. Nous avons précédemment montré que les cellules dendritiques plasmocytoïdes (pDCs) sont normalement absentes de la peau saine mais infiltrent rapidement la peau humaine ainsi que celle des souris après une blessure cutanée. Après avoir infiltré la peau, ces pDCs sont capables de détecter les acides nucléiques par l'expression des récepteurs de type Toll 7 et 9 ce qui les active à produire de 1' interféron (IFN) de type I. Ce processus est primordial pour la re- épithélisation des blessures cutanées. Cependant, les mécanismes conduisant à l'infiltration et à 1'activation des pDCs restent inconnus. Dans notre projet, nous montrons que la chimiokine CxcllO est responsable de l'infiltration des pDCs. De façon importante, nous démontrons que les neutrophiles qui infiltrent également la peau lésée sont la source majeure de cette chimiokine. La déplétion des neutrophiles abolit d'ailleurs le recrutement des pDCs confirmant ainsi que CxcllO produit par les neutrophiles est responsable de l'infiltration des pDCs dans la peau endommagée. De façon intéressante, nous avons trouvé que CxcllO en plus de son activité chimiotactique, est capable de former des complexes avec l'ADN et d'activer ainsi les pDCs à produire de l'IFN de type I. De plus, nous avons observé que les neutrophiles qui infiltrent la peau forment des Neutrophil Extracellular Traps (NETs). Ces NETs sont constitués de filaments extracellulaires d'ADN recouverts par de nombreuses protéines principalement d'origine granulaire. D'une manière frappante, le blocage de la NETose ou l'utilisation de souris déficientes pour la formation de NETs altère le recrutement et l'activation des pDCs ainsi que la réponse inflammatoire qui en découle ainsi que le processus de re-epithélisation qui s'ensuit. En prenant en compte toutes ces données, nos résultats démontrent que suite à une blessure de la peau, les neutrophiles par la production de CxcllO contrôlent l'infiltration des pDCs dans la peau lésée et par la formation de NETs, promeuvent l'activation des pDCs. Notre étude fournit donc de nouvelles informations sur les mécanismes de guérison de la peau et ouvre de nouvelles perspectives thérapeutiques quant à la réparation tissulaire de la peau soit dans le but de l'amplifier ou de l'inhiber. -- The mechanisms that regulate healing of the injured skin are not well understood. We have previously shown that plasmacytoid dendritic cells (pDCs) are normally absent from the healthy skin, but rapidly infiltrate both murine and human skin upon injury. Upon skin infiltration, pDCs sense nucleic acids via TLR7/TLR9 and are activated to produce type I interferon (IFN), a process that is crucial for re-epithelialisation of skin wounds. However, the mechanisms that drive pDCs recruitment and activation in injured skin remain unclear. We show that CxcllO is responsible for pDCs infiltration. Importantly, we demonstrate that skin infiltrating neutrophils are the major source of this chemokine. Neutrophils depletion completely abrogated pDCs recruitment confirming that CxcllO- driven pDCs recruitment is controlled by neutrophils. Interestingly, CxcllO was also found to form complexes with DNA and to activate pDCs to produce Type I IFN in addition to its chemotactic activity. Moreover, we observed that infiltrating neutrophils release Neutrophils Extracellular Traps (NETs) composed of DNA filaments decorated with neutrophils-derived proteins. Strikingly, blocking NETosis or using mice deficient for NETs production impaired pDCs recruitment and activation as well as the subsequent inflammatory response and the re-epithelialisation process. Altogether, these data demonstrate that upon skin injury, neutrophils control pDCs infiltration into the injured skin by the release of CxcllO and via the production of NETs, they allow complex formation between CxcllO and NET-DNA leading to pDCs activation. Our findings provide new insights into the mechanisms of wound healing and open new avenues for potential therapeutic interventions to boost or inhibit wound repair in the skin.