T-cell-specific peroxisome proliferator-activated receptor gamma depletion inhibits T-cell apoptosis and improves survival of septic mice via an IL-2-dependent mechanism

Introduction: Immune paralysis with massive T-cell apoptosis is a central pathogenic event during sepsis and correlates with septic patient mortality. Previous observations implied a crucial role of peroxisome proliferator-activated receptor gamma (PPARγ) during T-cell apoptosis. Methods: To elucidate mechanisms of PPARγ-induced T-cell depletion, we used an endotoxin model as well as the caecal ligation and puncture sepsis model to imitate septic conditions in wild-type versus conditional PPARγ knockout (KO) mice. Results: PPARγ KO mice showed a marked survival advantage compared with control mice. Their T cells were substantially protected against sepsis-induced death and showed a significantly higher expression of the pro-survival factor IL-2. Since PPARγ is described to repress nuclear factor of activated T cells (NFAT) transactivation and concomitant IL-2 expression, we propose inhibition of NFAT as the underlying mechanism allowing T-cell apoptosis. Corroborating our hypothesis, we observed up-regulation of the pro-apoptotic protein BIM and downregulation of the anti-apoptotic protein Bcl-2 in control mice, which are downstream effector proteins of IL-2 receptor signaling. Application of a neutralizing anti-IL-2 antibody reversed the pro-survival effect of PPARγ-deficient T cells and confirmed IL-2-dependent apoptosis during sepsis. Conclusion: Apparently antagonizing PPARγ in T cells might improve their survival during sepsis, which concomitantly enhances defence mechanisms and possibly provokes an increased survival of septic patients

Bioengineering silicon quantum dot theranostics using a network analysis of metabolomic and proteomic data in cardiac ischemia

Metabolomic profiling is ideally suited for the analysis of cardiac metabolism in healthy and diseased states. Here, we show that systematic discovery of biomarkers of ischemic preconditioning using metabolomics can be translated to potential nanotheranostics. Thirty-three patients underwent percutaneous coronary intervention (PCI) after myocardial infarction. Blood was sampled from catheters in the coronary sinus, aorta and femoral vein before coronary occlusion and 20 minutes after one minute of coronary occlusion. Plasma was analysed using GC-MS metabolomics and iTRAQ LC-MS/MS proteomics. Proteins and metabolites were mapped into the Metacore network database (GeneGo, MI, USA) to establish functional relevance. Expression of 13 proteins was significantly different (p<0.05) as a result of PCI. Included amongst these was CD44, a cell surface marker of reperfusion injury. Thirty-eight metabolites were identified using a targeted approach. Using PCA, 42% of their variance was accounted for by 21 metabolites. Multiple metabolic pathways and potential biomarkers of cardiac ischemia, reperfusion and preconditioning were identified. CD44, a marker of reperfusion injury, and myristic acid, a potential preconditioning agent, were incorporated into a nanotheranostic that may be useful for cardiovascular applications. Integrating biomarker discovery techniques into rationally designed nanoconstructs may lead to improvements in disease-specific diagnosis and treatment