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Abdominal sepsis is associated with dysfunctional hemostasis. Thrombin generation (TG) is a rate-limiting step in systemic coagulation. Neutrophils can expell neutrophil extracellular traps (NETs) and/or microparticles (MPs) although their role in pathological coagulation remains elusive. Cecal ligation and puncture (CLP)-induced TG in vivo was reflected by a reduced capacity of plasma from septic animals to generate thrombin. Depletion of neutrophils increased TG in plasma from CLP mice. Sepsis was associated with increased histone 3 citrullination in neutrophils and plasma levels of cell-free DNA and DNA-histone complexes and administration of DNAse not only eliminated NET formation but also elevated TG in sepsis. Isolated NETs increased TG and co-incubation with DNAse abolished NET-induced formation of thrombin. TG triggered by NETs was inhibited by blocking factor XII and abolished in factor XII-deficient plasma but intact in factor VII-deficient plasma. Activation of neutrophils simultaneously generated large amount of neutrophil-derived MPs, which were found to bind to NETs via histone-phosphatidylserine interactions. These findings show for the first time that NETs and MPs physically interact, and that NETs might constitute a functional assembly platform for MPs. We conclude that NET-MP complexes induce TG via the intrinsic pathway of coagulation and that neutrophil-derived MPs play a key role in NET-dependent coagulation.

Background and Aims The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9 −/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. Results In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9 −/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9 −/− mice, confirming target specificity. Conclusion Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis. Graphical Abstract

Extracellular vesicles (EVs) play a crucial role in intercellular communication by transferring bioactive molecules from donor to recipient cells. As a result, EV fusion leads to the modulation of cellular functions and has an impact on both physiological and pathological processes in the recipient cell. This study explores the impact of EV fusion on cellular responses to inflammatory signaling. Our findings reveal that fusion renders non-responsive cells susceptible to inflammatory signaling, as evidenced by increased NF-κB activation and the release of inflammatory mediators. Syntaxin-binding protein 1 is essential for the merge and activation of intracellular signaling. Subsequent analysis show that EVs transfer their functionally active receptors to target cells, making them prone to an otherwise unresponsive state. EVs in complex with their agonist, require no further stimulation of the target cells to trigger mobilization of NF-κB. While receptor antagonists were unable to inhibit NF-κB activation, blocking of the fusion between EVs and their target cells with heparin mitigated inflammation in mice challenged with EVs. Extracellular vesicles (EVs) play a crucial role in intercellular communication by transferring bioactive molecules from donor to recipient cells. Here, the authors show that EVs play a crucial role in activating immune responses through cell fusion, shedding light on their impact on inflammation.

Serum Amyloid A (SAA) proteins are acute-phase reactants with critical roles in sterile and bacterial inflammation. Through in vitro and in vivo experiments, we demonstrate that SAA proteins amplify cytokine and chemokine responses during sterile inflammation and enhance bacterial clearance in infectious conditions. Mechanistically, SAA proteins augment NF-κB signaling, driving pro and anti-inflammatory mediator production. SAA -/- mice carrying a deletion of the Saa1 , Saa2 , Saa3 , and Saa4 serum amyloid A genes have better survival rates in sterile sepsis but are more prone to bacterial sepsis than their SAA +/+ counterparts, emphasizing their dual functionality in immune regulation. Overexpression of Saa1 , Saa2 , Saa3 , and Saa4 in macrophages enhances NF-κB-mediated pro-inflammatory cytokine production and bacterial clearance during infection. Together, our results show that SAA proteins are key modulators of inflammation, with distinct mechanisms tailored to sterile and infectious contexts.

The plasma proteome is highly dynamic and variable, composed of proteins derived from surrounding tissues and cells. To investigate the complex processes that control the composition of the plasma proteome, we developed a mass spectrometry-based proteomics strategy to infer the origin of proteins detected in murine plasma. The strategy relies on the construction of a comprehensive protein tissue atlas from cells and highly vascularized organs using shotgun mass spectrometry. The protein tissue atlas was transformed to a spectral library for highly reproducible quantification of tissue-specific proteins directly in plasma using SWATH-like data-independent mass spectrometry analysis. We show that the method can determine drastic changes of tissue-specific protein profiles in blood plasma from mouse animal models with sepsis. The strategy can be extended to several other species advancing our understanding of the complex processes that contribute to the plasma proteome dynamics. Sepsis can lead to multiple organ failure that could potentially be reflected by change in plasma protein abundance. Here the authors describe a proteomics strategy that allows the determination of plasma proteins tissue origin in a quantitative manner for use as biomarkers—illustrated in a mouse model of sepsis.

Hemostasis requires conversion of fibrinogen to fibrin fibers that generate a characteristic network, interact with blood cells, and initiate tissue repair. The fibrin network is porous and highly permeable, but the spatial arrangement of the external clot face is unknown. Here we show that fibrin transitioned to the blood-air interface through Langmuir film formation, producing a protective film confining clots in human and mouse models. We demonstrated that only fibrin is required for formation of the film, and that it occurred in vitro and in vivo. The fibrin film connected to the underlying clot network through tethering fibers. It was digested by plasmin, and formation of the film was prevented with surfactants. Functionally, the film retained blood cells and protected against penetration by bacterial pathogens in a murine model of dermal infection. Our data show a remarkable aspect of blood clotting in which fibrin forms a protective film covering the external surface of the clot, defending the organism against microbial invasion.

Heparin-binding protein (HBP) is released by granulocytes and has been shown to increase vascular permeability in experimental investigations. Increased vascular permeability in the lungs can lead to fluid accumulation in alveoli and respiratory failure. A generalized increase in vascular permeability leads to loss of circulating blood volume and circulatory failure. We hypothesized that plasma concentrations of HBP on admission to the intensive care unit (ICU) would be associated with decreased oxygenation or circulatory failure. This is a prospective, observational study in a mixed 8-bed ICU. We investigated concentrations of HBP in plasma at admission to the ICU from 278 patients. Simplified acute physiology score (SAPS) 3 was recorded on admission. Sequential organ failure assessment (SOFA) scores were recorded daily for three days. Median SAPS 3 was 58.8 (48-70) and 30-day mortality 64/278 (23%). There was an association between high plasma concentrations of HBP on admission with decreased oxygenation (p<0.001) as well as with circulatory failure (p<0.001), after 48-72 hours in the ICU. There was an association between concentrations of HBP on admission and 30-day mortality (p = 0.002). ROC curves showed areas under the curve of 0,62 for decreased oxygenation, 0,65 for circulatory failure and 0,64 for mortality. A high concentration of HBP in plasma on admission to the ICU is associated with respiratory and circulatory failure later during the ICU care period. It is also associated with increased 30-day mortality. Despite being an interesting biomarker for the composite ICU population it's predictive value at the individual patient level is low.

Hemostasis is a sensitive and tightly regulated process, involving vascular endothelium and blood cells, as well as factors of the coagulation and fibrinolytic cascades. In severe and invasive infectious diseases, the equilibrium between the procoagulant and anticoagulant status of the host may change dramatically and can induce life-threatening complications. A growing body of evidence suggests that the contact system, also known as the intrinsic pathway of coagulation or kallikrein/kinin system, participate in these processes. Contact activation leads to the release of the highly potent proinflammatory peptide bradykinin and initiates the intrinsic pathway of coagulation. Several studies have shown a systemic activation of the contact system in animal models of severe bacterial infections, and similar findings were also reported when monitoring patients suffering from sepsis, severe sepsis, or septic shock. Complications resulting from a systemic activation of the contact system are pathologically high levels of bradykinin, consumption of contact factors, and a subsequent induction of inflammatory reactions. These conditions may contribute to serious complications such as hypotension and vascular leakage. Here, we summarize the state of the art in this field of research with a focus on the contact system, and we also discuss a potential role for the contact system as a target for the development of novel antimicrobial strategies.

Initial differential diagnosis and prognosis for patients admitted to intensive care with suspected sepsis remain arduous. Hepcidin has emerged as a potential biomarker for sepsis. Here we report data on the relevance of levels of hepcidin versus other biomarkers as a diagnostic and prognostic tool for sepsis. 164 adult patients admitted to the intensive care unit (ICU) within 24 h upon arrival to the hospital were included. Blood samples collected daily for seven consecutive days and hepcidin levels, heparin binding protein (HBP) levels and standard biomarkers were determined. Blood cultures were initiated at inclusion. Clinical scores were evaluated daily and mortality after 28- and 180-days was recorded. One hundred of the patients were found to fulfil the criteria for sepsis whereas 64 did not. Hepcidin levels at admission were significantly higher in the septic than in the non-septic patients. In septic patients hepcidin levels declined significantly already at 24 h followed by a steady decline. A significant negative correlation was observed between hepcidin levels and SAPS 3 in patients with sepsis. Hepcidin levels at inclusion were significantly higher among septic patients that survived 180-days and predicted mortality. Our data show that hepcidin levels are indicative of sepsis in patients admitted to the ICU and has a prognostic value for mortality.