Introduction: Lymphocyte apoptosis and monocyte dysfunction play a pivotal role in sepsis-induced immunosuppression. Programmed death-1 (PD1) and its ligand programmed death ligand-1 (PD-L1) exert inhibitory function by regulating the balance among T cell activation, tolerance, and immunopathology. PD-1 deficiency or blockade has been shown to improve survival in murine sepsis. However, PD-L1 and PD-1 differ in their expression patterns and the role of PD-L1 in sepsis-induced immunosuppression is still unknown. Methods: Sepsis was induced in adult C57BL/6 male mice via cecal ligation and puncture (CLP). The expression of PD-1 and PD-L1 expression on peripheral T cells, B cells and monocytes were measured 24 hours after CLP or sham surgery. Additionally, the effects of anti-PD-L1 antibody on lymphocyte number, apoptosis of spleen and thymus, activities of caspase-8 and caspase-9, cytokine production, bacterial clearance, and survival were determined. Results: Expression of PD-1 on T cells, B cells and monocytes and PD-L1 on B cells and monocytes were up-regulated in septic animals compared to sham-operated controls. PD-L1 blockade significantly improved survival of CLP mice. Anti-PD-L1 antibody administration prevented sepsis-induced depletion of lymphocytes, increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production, decreased IL-10 production, and enhanced bacterial clearance. Conclusions: PD-L1 blockade exerts a protective effect on sepsis at least partly by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Anti-PD-L1 antibody administration may be a promising therapeutic strategy for sepsis-induced immunosuppression.

Introduction: Studies on the role of programmed death-1(PD-1) and its main ligand (PD-L1) during experimental models of sepsis have shown that the PD-1/PD-L1 pathway plays a pathologic role in altering microbial clearance, the innate inflammatory response and accelerated apoptosis in sepsis. However, the expression of PD-1 and PD-L1 and their role during the development of immune suppression in septic patients have not been elucidated. The present study was designed to determine whether the expression of PD-1 and PD-L1 is upregulated in septic shock patients and to explore the role of this pathway in sepsis-induced immunosuppression. Methods: Nineteen septic shock patients and 22 sex-matched and age-matched healthy controls were prospectively enrolled. Apoptosis in lymphocyte subpopulations and PD-1/PD-L1 expression on peripheral T cells, B cells and monocytes were measured using flow cytometry. Apoptosis of T cells induced by TNFα or T-cell receptor ligation in vitro and effects of anti-PD-L1 antibody administration were measured by flow cytometry. CD14⁺ monocytes of septic shock patients were purified and incubated with either lipopolysaccharide, anti-PD-L1 antibody, isotype antibody, or a combination of lipopolysaccharide and anti-PD-L1 antibody or isotype antibody. Supernatants were harvested to examine production of cytokines by ELISA. Results: Compared with healthy controls, septic shock induced a marked increase in apoptosis as detected by the annexin-V binding and active caspase-3 on CD4⁺ T cells, CD8⁺ T cells and CD19⁺ B cells. Expression of PD-1 on T cells and of PD-L1 on monocytes was dramatically upregulated in septic shock patients. PD-1/PD-L1 pathway blockade in vitro with anti-PD-L1 antibody decreased apoptosis of T cells induced by TNFα or T-cell receptor ligation. Meanwhile, this blockade potentiated the lipopolysaccharide-induced TNFα and IL-6 production and decreased IL-10 production by monocytes in vitro. Conclusions: The expression of PD-1 on T cells and PD-L1 on monocytes was upregulated in septic shock patients. The PD-1/PD-L1 pathway might play an essential role in sepsis-induced immunosuppression.

Introduction: To investigate the effects of G-CSF or GM-CSF therapy in non-neutropenic patients with sepsis. Methods: A systematic literature search of Medline, Embase and Cochrane Central Register of Controlled Trials was conducted using specific search terms. A manual review of references was also performed. Eligible studies were randomized control trials (RCTs) that compared granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) therapy with placebo for the treatment of sepsis in adults. Main outcome measures were all-cause mortality at 14 days and 28 days after initiation of G-CSF or GM-CSF therapy, in-hospital mortality, reversal rate from infection, and adverse events. Results: Twelve RCTs with 2,380 patients were identified. In regard to 14-day mortality, a total of 9 death events occurred among 71 patients (12.7%) in the treatment group compared with 13 events among 67 patients (19.4%) in the placebo groups. Meta-analysis showed there was no significant difference in 28-day mortality when G-CSF or GM-CSF were compared with placebo (relative risks (RR) = 0.93, 95% confidence interval (CI): 0.79 to 1.11, P = 0.44; P for heterogeneity = 0.31, I² = 15%). Compared with placebo, G-CSF or GM-CSF therapy did not significantly reduce in-hospital mortality (RR = 0.97, 95% CI: 0.69 to 1.36, P = 0.86; P for heterogeneity = 0.80, I² = 0%). However, G-CSF or GM-CSF therapy significantly increased the reversal rate from infection (RR = 1.34, 95% CI: 1.11 to 1.62, P = 0.002; P for heterogeneity = 0.47, I² = 0%). No significant difference was observed in adverse events between groups (RR = 0.93, 95% CI: 0.70 to 1.23, P = 0.62; P for heterogeneity = 0.03, I² = 58%). Sensitivity analysis by excluding one trial did not significantly change the results of adverse events (RR = 1.05, 95% CI: 0.84 to 1.32, P = 0.44; P for heterogeneity = 0.17, I² = 36%). Conclusions: There is no current evidence supporting the routine use of G-CSF or GM-CSF in patients with sepsis. Large prospective multicenter clinical trials investigating monocytic HLA-DR (mHLA-DR)-guided G-CSF or GM-CSF therapy in patients with sepsis-associated immunosuppression are warranted.

Sepsis is a heterogeneous syndrome induced by a dysregulated host response to infection. Glycolysis plays a role in maintaining the immune function of macrophages, which is crucial for severely septic patients. However, how the pathways that link glycolysis and macrophages are regulated is still largely unknown. Here, we provide evidence to support the function of KLF14, a novel Krüppel-like transcription factor, in the regulation of glycolysis and the immune function of macrophages during sepsis. KLF14 deletion led to significantly increased mortality in lethal models of murine endotoxemia and sepsis. Mechanistically, KLF14 decreased glycolysis and the secretion of inflammatory cytokines by macrophages by inhibiting the transcription of HK2. In addition, we confirmed that the expression of KLF14 was upregulated in septic patients. Furthermore, pharmacological activation of KLF14 conferred protection against sepsis in mice. These findings uncover a key role of KLF14 in modulating the inflammatory signaling pathway and shed light on the development of KLF14-targeted therapeutics for sepsis.

Introduction: Early diagnosis of sepsis is vital to the clinical course and outcome of septic patients. Recently, soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) appears to be a potential marker of infection. The objective of this systematic review and meta-analysis was to evaluate the accuracy of plasma sTREM-1 for sepsis diagnosis in systemic inflammatory patients. Methods: A systematic literature search of PubMed, Embase and Cochrane Central Register of Controlled Trials was performed using specific search terms (up to 15 October 2012). Studies were included if they assessed the accuracy of plasma sTREM-1 for sepsis diagnosis in adult patients with systemic inflammatory response syndrome (SIRS) and provided sufficient information to construct a 2 X 2 contingency table. Results: Eleven studies with a total of 1,795 patients were included. The pooled sensitivity and specificity was 79% (95% confidence interval (CI), 65 to 89) and 80% (95% CI, 69 to 88), respectively. The positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 4.0 (95% CI, 2.4 to 6.9), 0.26 (95% CI, 0.14 to 0.48), and 16 (95% CI, 5 to 46), respectively. The area under the curve of the summary receiver operator characteristic was 0.87 (95% CI, 0.84 to 0.89). Meta-regression analysis suggested that patient sample size and assay method were the main sources of heterogeneity. Publication bias was suggested by an asymmetrical funnel plot (P = 0.02). Conclusions: The present meta-analysis showed that plasma sTREM-1 had a moderate diagnostic performance in differentiating sepsis from SIRS. Accordingly, plasma sTREM-1 as a single marker was not sufficient for sepsis diagnosis in systemic inflammatory patients.

Introduction: Early identification of septic patients at high risk of dying remains a challenge. The prognostic role of brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) in septic patients remains controversial. The purpose of this systematic review and meta-analysis was to investigate the value of elevated BNP or NT-proBNP in predicting mortality in septic patients. Methods: PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched (up to February 18, 2011). Studies were included if they had prospectively collected data on all-cause mortality in adult septic patients with either plasma BNP or NT-proBNP measurement. Studies that failed to construct a 2 × 2 table of results were excluded. Two authors independently determined the validity of included studies and extracted data. Results: 12 studies with a total of 1,865 patients were included. Elevated natriuretic peptides were significantly associated with increased risk of mortality (odds ratio (OR) 8.65, 95% confidence interval (CI) 4.94 to 15.13, P < 0.00001). The association was consistent for BNP (OR 10.44, 95% CI 4.99 to 21.58, P < 0.00001) and NT-proBNP (OR 6.62, 95% CI 2.68 to 16.34, P < 0.0001). The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 79% (95% CI 75 to 83), 60% (95% CI 57 to 62), 2.27 (95% CI 1.83 to 2.81) and 0.32 (95% CI 0.22 to 0.46), respectively. Conclusions: Our results suggested that an elevated BNP or NT-proBNP level may prove to be a powerful predictor of mortality in septic patients. Future larger and more adequately powered prospective studies are warranted to clarify the assay standardization, the optimal cut-off, and the prognostic value of BNPs in conjunction with other biomarkers.