Impaired Circulating Antibody-Secreting Cells Generation Predicts the Dismal Outcome in the Elderly Septic Shock Patients.

Purpose: Sepsis is a condition that derives from a dysregulated host response to infection. Although B lymphocytes play a pivotal role in immune response, little is known about status of their terminally differentiated cells, antibody-secreting cells (ASCs) during immunosuppressive phase of sepsis, especially in elderly patients. Our aim was to extensively characterize the immune functions of ASCs in elderly septic patients. Patients and Methods: Clinical and laboratory data were collected on days 1, 3, and 7 of hospitalization. Circulating ASCs were evaluated by flow cytometry from fresh whole blood in elderly septic patients at the onset of disease. RNA sequencing analyzed ASCs gene expression profile. Receiver operating characteristic (ROC) curve analysis and logistic regression predicted the survival rate of 28-day mortality. Results: A total of 103 septic patients were enrolled. The number and proportion of ASCs among total lymphocytes dramatically increased in septic patients, and RNA sequencing analysis showed that ASCs from septic patients exhibited a different gene expression profile. Furthermore, we found these ASCs could promote the function of T cells. Logistic regression analysis showed ASCs population was an independent outcome predictor in septic shock patients. Conclusion: Our study revealed the complex nature of immune disorders in sepsis and identified circulating ASCs population as a useful biomarker for predicting mortality in elderly septic patients, which provided a novel clue to combat this severe disease.

Platelets Derived Transthyretin Participate in The Development of Sepsis Associated Acute Kidney Injury by Inducing Oxidative Stress and Apoptosis of Renal Tubular Epithelial Cells.

ABSTRACT: The pathophysiology of sepsis-associated acute kidney injury (S-AKI) is not well elucidated. Platelets have been reported to play a critical role in the pathogenesis of AKI, but the true mechanism remains unknown. Herein, we established a mouse model of S-AKI by cecal ligation and puncture (CLP). Ticagrelor was given 24 h before and after CLP by gastric gavage. Platelets were isolated and analyzed by the label-free proteome approach to identify platelet-derived damage-associated molecular patterns (DAMPs). Our results demonstrated that, among all differentially expressed proteins (DEPs), platelet-derived transthyretin (TTR) exerted effects in S-AKI. To examine the direct effects of platelet TTR on human renal proximal tubule epithelial (HK2) cells damage, platelets were co-cultured with HK2 cells. The results indicated that platelet TTR can cause reactive oxygen species production and apoptosis in HK2 cells. Further research found that platelet TTR can also result in increased levels of mRNA and protein for protein kinase B (AKT), phosphatidylinositol 3-kinase (PI3K), and extracellular regulated protein kinase (ERK), as analyzed by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. In conclusion, platelet-derived TTR may be one kind of DAMPs that plays an important role in the development of S-AKI.

Novel pharmacological inhibition of EZH2 attenuates septic shock by altering innate inflammatory responses to sepsis.

The function of histone methyltransferase enhancer of zeste homolog 2 (EZH2) in sepsis remains unknown. We reported here that the expression of EZH2 and H3K27me3 was significantly upregulated in the circulation of septic patients, whereas patients who survived presented downregulated the expression of EZH2 on CD14+ monocytes. We further identified increased expression of EZH2 in the circulation, peritoneal fluid, and septic lungs from CLP mice. 3-DZNeP treated CLP mice improved mortality and protected from organ injury. EZH2 inhibition not only suppressed the activation of inflammatory cells and release of cytokines in the circulation and infectious sites, but also promoted bacteria clearance and replenished the circulating monocyte and neutrophil pool from bone marrow. Blockage of EZH2 also suppressed the progression of lung injury and alleviated inflammation by decreasing the pulmonary cell apoptosis, reducing inflammatory cells infiltration and cytokines release through inhibition of the STAT3 signaling pathway and recovery of PPARγ activation. In addition, EZH2 inhibitor blunted macrophage M1 polarization by SOCS3/STAT1 pathway. Overall, these data suggest that EZH2 could be a potential biomarker predicting clinical outcome and a new target for therapeutic interference in sepsis.