Daily Sepsis Research Analysis

Neutrophils play a critical role in sepsis-induced acute lung injury (ALI). Extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, promotes neutrophil heterogeneity. While delta-like ligand 4 (DLL4) expression has been studied in various cell populations, its expression in neutrophils and impact on inflammation remain unknown. Here, we discovered that eCIRP induces DLL4+ neutrophils. These neutrophils trigger PANoptosis, a novel proinflammatory form of cell death initiated by Z-DNA-binding protein-1 (ZBP1) in pulmonary vascular endothelial cells (PVECs). In sepsis, DLL4+ neutrophils increase in the blood and lungs, upregulating ZBP1, cleaved gasdermin D, cleaved caspase-3, and phosphorylated MLKL, all of which are markers of PANoptosis, exacerbating ALI. DLL4 binds to Notch1 on PVECs and activates Notch1 intracellular domain to increase ZBP1-mediated endothelial PANoptosis. We discovered what we believe to be a novel Notch1-DLL4 inhibitor (NDI), derived from Notch1 to specifically block this interaction. Our findings reveal that NDI reduced endothelial PANoptosis in vitro and in vivo, attenuated pulmonary injury induced by DLL4+ neutrophils, and decreased lung water content and permeability, indicating improved barrier function. NDI also reduced serum injury and inflammatory markers and improved survival rate in sepsis. These findings underscore the Notch1-DLL4 pathway's critical role in DLL4+ neutrophil-mediated ALI. Targeting the Notch1-DLL4 interaction with an NDI represents a promising therapeutic strategy for sepsis-induced ALI.

BACKGROUND: Our previous animal studies suggested the critical role of type I interferons (IFNβ) and high-mobility group box 1 (HMGB1) axis in coagulation; however, the predictive value of IFNβ/HMGB1 for the clinical onset of septic disseminated intravascular coagulation (DIC) remains unknown. OBJECTIVES: This study aims to further elaborate on the pathogenesis of sepsis-associated DIC and identify potential biomarkers suitable for the early prediction of DIC. METHODS: The plasma levels of IFNβ/HMGB1 were determined in septic patients without DIC at admission. The onset of septic DIC was assessed 48 h thereafter. We subsequently compared the leukocyte transcriptomes of non-DIC with and DIC patients. A series of gene-modified mice, including IFNα/βR1 RESULTS: The plasma level of IFNβ but not HMGB1 in septic patients shows a consistent correlation with the onset of DIC. We identified a HMGB1-bypassing signaling pathway where IFNβ stimulates macrophages to express high levels of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in response to gram-negative bacteria. Deletion of Malat1 specifically in macrophages restores GSH (glutathione) exhaustion and enhances GPX4 activity by maintaining YY1-mediated Hba-a1 expression, which dampens lipopolysaccharide (LPS) internalization and caspase-11 activation, and suppresses caspase-11/GSDMD-dependent phosphatidylserine (PS) exposure, thereby protecting against bacteria-induced coagulation. CONCLUSION: Our study unveils a novel immunocoagulation pathway: MALAT1 fuels caspase-11-dependent coagulation by inhibiting GPX4 activity, which provides new insights into the coagulation mechanisms in bacterial sepsis.

During the progression of severe sepsis, the oxidized mitochondrial DNA (mtDNA) in macrophages is cleaved by flap-structure-specific endonuclease 1 (FEN1) into small fragments, which are subsequently released into the cytosol and extracellular space to activate multiple pro-inflammatory signaling pathways such as NLRP3 inflammasome, cGAS-STING, and TLR9-NF-κB. Herein, biomimetic nanocomplexes (NCs) partially cloaked with macrophage membrane (MM) are developed to efficiently deliver FEN1 siRNA (siFEN1) into macrophages for sepsis management. To construct the NCs, membrane-penetrating, helical polypeptide (PG) first condenses siFEN1 and forms the cationic inner core, which is further coated with MM. By optimizing the membrane protein/siFEN1 weight ratios, partial membrane coating can be achieved, which enables the formation of NCs with both enhanced serum stability and efficient macrophage uptake efficiency. After systemic administration in cecal ligation and puncture-induced sepsis mice, the NCs exhibit prolonged blood circulation time and effective accumulation to the inflamed tissues, facilitated by MM-mediated charge neutralization of the cationic nanocore and inflammation homing. Subsequently, the NCs are efficiently internalized by macrophages through the interaction between the partially exposed polycationic core and the target cell membranes, provoking robust FEN1 silencing to suppress mtDNA fragmentation and leakage. Consequently, the NCs effectively restore immune homeostasis in sepsis mice, thereby mitigating cytokine storm and alleviating multiple organ failure.