Daily Sepsis Research Analysis

Cells of the immune system operate in dynamic microenvironments where the timing, concentration, and order of signaling molecules constantly change. Despite this complexity, immune cells manage to communicate accurately and control inflammation and infection. It is unclear how these dynamic signals are encoded and decoded and if individual cells retain the memory of past exposure to inflammatory molecules. Here, we use live-cell analysis, ATAC sequencing, and an in vivo model of sepsis to show that sequential inflammatory signals induce memory in individual macrophages through reprogramming the nuclear factor κB (NF-κB) network and the chromatin accessibility landscape. We use transcriptomic profiling and deep learning to show that transcription factor and chromatin dynamics coordinate fine-tuned macrophage responses to new inflammatory signals. This work demonstrates how macrophages retain the memory of previous signals despite single-cell variability and elucidates the mechanisms of signal-induced memory in dynamic inflammatory conditions like sepsis.

BACKGROUND: Extracellular vesicles derived from pericytes (PCEVs) have been shown to improve vascular permeability, with their therapeutic effects attributed to the presence of pro-regenerative molecules. We hypothesized that angiopoietin 1 (Angpt1) carried by PCEVs contributes to their therapeutic effects after sepsis. METHODS: A cecal ligation and puncture (CLP)-induced sepsis rat model was used in vivo, and the effects of PCEVs on vascular endothelial cells were studied in vitro. First, proteomic and Gene Ontology enrichment analyses were performed to analyze the therapeutic mechanism of PCEVs, revealing that the angiogenesis-related protein Angpt1 was highly expressed in PCEVs. We then down-regulated Angpt1 in PCEVs. The role of PCEV-carried Angpt1 on intestinal barrier function, PCs recruitment, and inflammatory cytokines was measured by using septic Sprague-Dawley rats and platelet-derived growth factor receptor beta (PDGFR-β)-Cre + mT/mG transgenic mice. RESULTS: PCEVs significantly improved vascular permeability, proliferation, and angiogenesis in CLP-induced gut barrier injury both in vivo and in vitro. Further studies have shown that PCEVs exert a protective effect on intestinal barrier function and PC recruitment. Additionally, PCEVs reduced serum inflammatory factor levels. Our data also demonstrated that the protein levels of phospho-PI3K and phospho-Akt both increased after PCEVs administration, whereas knocking out Angpt1 suppressed the protective effects of PCEVs through decreased activation of PI3K/Akt signaling. CONCLUSION: PCEVs protect against sepsis by regulating the vascular endothelial barrier, promoting PC recruitment, protecting intestinal function, and restoring properties via activation of the Angpt1/PI3K/AKT pathway.

Chronic inflammation is mainly characterized by the release of proinflammatory cytokines (cytokine storm) and reactive oxygen/nitrogen species. Sepsis is a life-threatening condition resulting from the successive chronic inflammatory responses toward infection, leading to multiple organ failure and, ultimately, death. As inflammation and oxidative stress are known to nourish each other and initiate an uncontrolled immune response, inhibiting the cross-talk between the inflammatory response using anti-inflammatory drugs and oxidative stress using antioxidants can be a promising strategy to target sepsis. Here, we present the engineering of chimeric nanomicelles (NMs) using an ester-linked polyethylene glycol-derived lithocholic acid-drug conjugate using dexamethasone (DEX), a potent glucocorticoid possessing anti-inflammatory properties, and vitamin E (VITE), an antioxidant to target oxidative stress. Interestingly, these chimeric DEX-VITE NMs show enhanced accumulation at the inflamed sites driven by enhanced permeation and retention effect and mitigate localized acute inflammation in paw, lung, and liver inflammation models. We further demonstrated the efficacy of these NMs in mitigating LPS-induced endotoxemia and CLP-induced microbial sepsis, conferring survival advantages. DEX-VITE NMs also modulate immune homeostasis by decreasing the infiltration of total immune cells, neutrophils, and overall macrophages. Finally, administration of DEX-VITE NMs also reduces the release of proinflammatory cytokines and prevents vascular damage, two critical factors of sepsis pathogenesis. Therefore, this therapeutic approach of chimeric NMs can effectively deliver steroids and antioxidants to mitigate uncontrolled localized and systemic inflammation.