Sepsis is currently a leading cause of death in hospital intensive care units. Previous studies suggest that the pathophysiology of sepsis involves the hyperactivation of complex pro-inflammatory cascades that include the activation of various immune cells and the exuberant secretion of pro-inflammatory cytokines by these cells. Natural killer T-cells (NKT) are a sub-lineage of T cells that share characteristics of conventional T cells and NK cells, and bridge innate and adaptive immunity. More recently, NKT cells have been implicated in microbial immunity, including the onset of sepsis. Moreover, apolipoprotein E (apoE), a component of triglyceride-rich lipoproteins, has been shown to be protective in endotoxemia and gram-negative infections in addition to its well-known role in lipid metabolism. Here, we will review the role of NKT cells in sepsis and septic shock, the immunoregulatory role of apoE in the host immune response to infection, and propose a mechanism for this immunoregulation.
"(C–D) The graphs show the percentage (C) and absolute cell numbers (D) of the indicated blood T-cell subsets. polymicrobial sepsis   . Interestingly, unlike liver we did not find any change in NKT cells after CLP in any other organ studied (data not shown). "
[Show abstract][Hide abstract] ABSTRACT: Among immune cells in responding to sepsis, macrophages and neutrophils have been extensively studied, while the contribution of T lymphocytes and natural killer T (NKT) cells is less well characterized. Here we monitored tissue specific changes of T cell subsets in male C57BL/6 mice subjected to sham operation or cecal ligation and puncture (CLP) to induce polymicrobial sepsis. Thymus, spleen, liver, lungs and blood were processed and analyzed 20h later. Total lymphocyte count showed a significant reduction in septic thymus, spleen and blood but not in lungs and liver. The septic thymi were hypocellular with severe reduction in cell numbers of immature CD4(+)CD8(+) subset. CD4(+) T and CD8(+) T lymphocyte numbers in septic spleens were also significantly reduced, but the frequency of CD4(+)CD25(+) Tregs was significantly increased. In addition, naïve and Tcm CD4(+) T cell numbers were significantly reduced in the septic spleens. By contrast, in septic liver the CD8(+) T cell numbers were significantly increased, whereas NKT cell numbers were reduced, but more activated with increased CD69 and CD25 expression. In the septic lungs, the CD4(+) T and CD8(+) T cell numbers showed no significant change, whereas they were severely reduced in the septic blood. Overall, this study provides important information on the alterations of different T-cell subsets in various tissues after sepsis.
"NKT cells are potent producers of proinflammatory mediators such as IFN-γ; they are capable of activating macrophages, NK cells, dendritic cells, and effector T cells and possess cytotoxic effector activity . Altogether, they have been thought to be significant promoters of the dysregulated septic response . Recently, Heffernan et al. have demonstrated that invariant NKT (iNKT) cells, a type of NKT cells that express an invariant Vα24/Jα18 chain and a restricted β chain , are increased in sepsis and this is most pronounced in geriatric nonsurviving patients . "
[Show abstract][Hide abstract] ABSTRACT: Sepsis is a systemic inflammatory response syndrome due to infection. The incidence rate is estimated to be up to 19 million cases worldwide per year and the number of cases is rising. Infection triggers a complex and prolonged host response, in which both the innate and adaptive immune response are involved. The disturbance of immune system cells plays a key role in the induction of abnormal levels of immunoregulatory molecules. Furthermore, the involvement of effector immune system cells also impairs the host response to the infective agents and tissue damage. Recently, postmortem studies of patients who died of sepsis have provided important insights into why septic patients die and showed an extensive depletion of CD4 and CD8 lymphocytes and they found that circulating blood cells showed similar findings. Thus, the knowledge of the characterization of circulating lymphocyte abnormalities is relevant for the understanding of the sepsis pathophysiology. In addition, monitoring the immune response in sepsis, including circulating lymphocyte subsets count, appears to be potential biomarker for predicting the clinical outcome of the patient. This paper analyzes the lymphocyte involvement and dysfunction found in patients with sepsis and new opportunities to prevent sepsis and guide therapeutic intervention have been revealed.
BioMed Research International 08/2014; 2014:671087. DOI:10.1155/2014/671087 · 2.71 Impact Factor
"Previous studies from our laboratory and from others have demonstrated that NK and CD8+ T cells contribute to systemic inflammation and physiologic dysfunction during sepsis or polytrauma [17,42-44]. Hu and colleagues reported that NKT cells play a functional role in the pathogenesis of CLP-induced septic shock while other investigators have shown that NKT cells facilitate systemic inflammation during lethal challenge with lipopolysaccharide (LPS) [45,46]. Evidence indicates that CXCR3+ NK cells migrate into the inflamed peritoneal cavity from blood and spleen early during the course of CLP-induced sepsis. "
[Show abstract][Hide abstract] ABSTRACT: Introduction
The chemokine CXCL10 is produced during infection and inflammation to activate the chemokine receptor CXCR3, an important regulator of lymphocyte trafficking and activation. The goal of this study was to assess the contributions of CXCL10 to the pathogenesis of experimental septic shock in mice.
Septic shock was induced by cecal ligation and puncture (CLP) in mice resuscitated with lactated Ringer’s solution and, in some cases, the broad spectrum antibiotic Primaxin. Studies were performed in CXCL10 knockout mice and mice treated with anti-CXCL10 immunoglobulin G (IgG). Endpoints included leukocyte trafficking and activation, core body temperature, plasma cytokine concentrations, bacterial clearance and survival.
CXCL10 was present at high concentrations in plasma and peritoneal cavity during CLP-induced septic shock. Survival was significantly improved in CXCL10 knockout (CXCL10KO) mice and mice treated with anti-CXCL10 IgG compared to controls. CXCL10KO mice and mice treated with anti-CXCL10 IgG showed attenuated hypothermia, lower concentrations of interleukin-6 (IL-6) and macrophage inhibitory protein-2 (MIP-2) in plasma and lessened natural killer (NK) cell activation compared to control mice. Compared to control mice, bacterial burden in blood and lungs was lower in CXCL10-deficient mice but not in mice treated with anti-CXCL10 IgG. Treatment of mice with anti-CXCL10 IgG plus fluids and Primaxin at 2 or 6 hours after CLP significantly improved survival compared to mice treated with non-specific IgG under the same conditions.
CXCL10 plays a role in the pathogenesis of CLP-induced septic shock and could serve as a therapeutic target during the acute phase of septic shock.
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