Apolipoprotein E-Mediated Immune Regulation in Sepsis

Department of Surgery, University of California School of Medicine, San Francisco, CA 94110, USA.
The Journal of Immunology (Impact Factor: 4.92). 08/2008; 181(2):1399-408. DOI: 10.4049/jimmunol.181.2.1399
Source: PubMed


Lipids and lipoproteins have emerged as key constituents of the immune response to microbial infection. We, therefore, sought to understand the complex interaction between lipoprotein metabolism and sepsis. Apolipoprotein E (apoE), a component of plasma lipoproteins, has been suggested to bind and traffic Ags for NKT cell activation. However, apoE's role in sepsis has not been demonstrated. In this study, we examined the effect of exogenous apoE in a rat model of septic peritonitis, induced by cecal ligation and puncture. We demonstrate that 48 h after serial injections of apoE, septic mortality increased in a dose-dependent manner. While sepsis resulted in increased splenic and decreased hepatic and circulating NKT cell populations, serial injections of apoE for 24 h after cecal ligation and puncture increased the frequency, cell number, and BrdU uptake in splenic and hepatic NKT cell populations, while concomitantly depleting these populations in the circulation. These changes were correlated with elevated alanine amino transferase levels, an indicator of liver injury. Interestingly, while sepsis increased hepatic T cell apoptosis and necrosis, apoE reversed these changes. apoE also promoted increases in predominantly Th1 cytokine levels in sera and a decrease in IL-4, the main NKT cell-derived Th2 cytokine. Consequently, apoE treatment is associated with increased sepsis-induced mortality, and increased NKT cell frequency and proliferation in the liver and spleen, with concomitant decreases in these NKT cell parameters in the peripheral circulation. apoE treatment also promoted a Th1 cytokine response, increased the degree of liver injury, and decreased apoptosis in hepatic lymphocytes.

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Available from: Hobart W Harris, Nov 14, 2014
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    • "Binding of LPS to the HDL particles is thought to be part of the innate immune response. Sepsis also increases apoE-enriched HDL particles; however, apoE has both been shown to protect against LPSinduced sepsis by binding LPS [7], but also to accelerate cytokine production and increase mortality in animal models [8]. ApoL, another apolipoprotein on HDL particles having anti-trypanolytic effects, also plays an important role in the innate immune system [9]. "
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    ABSTRACT: Sepsis is one of the leading causes of mortality in non-cardiac intensive care units, and the need for markers of progression and severity are high. Also, treatment of sepsis is highly debated and potential new targets of treatment are of great interest. In the previous issue of Critical Care Kumaraswamy and colleagues have investigated whether plasma apolipoprotein M (apoM) is affected during different grades of sepsis, septic shock and systemic inflammatory response syndrome. Interestingly, plasma apoM was significantly decreased in all groups of patients with a relationship to severity of disease. This identifies apoM as a potential new biomarker in sepsis. It also underscores the possibility that altered high-density lipoprotein in sepsis patients can affect the course of disease. Thus, since apoM is the carrier of Sphingosine-1-P (S1P), a molecule with great influence on vascular barrier function, the study presented raises the interest and relevance for further studies of apoM and S1P in relation to sepsis and inflammation.
    Critical care (London, England) 05/2012; 16(3):126. DOI:10.1186/cc11320 · 4.48 Impact Factor
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    • "Binding of bacterial endotoxin to either HDL, LDL, or VLDL results in a redirection of endotoxin uptake from Kupffer cells to parenchymal hepatocytes where the endotoxin is deactivated [30]. ApoE facilitated sepsis-induced mortality in a dose-dependent manner and increased natural killer T-(NKT)-cell proliferation in the spleen [31]. ApoE deficient mice were markedly more susceptible to tuberculosis, evidenced by 100% mortality within 4 weeks of infection with tuberculosis [32]. "
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    ABSTRACT: Apolipoprotein E (apoE) is a multifunctional glycosylated protein characterized by its wide tissue distribution. Despite its importance in lipid transport and atherosclerosis pathogenesis, apoE is associated with neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson disease, and autoimmune disorders such as multiple sclerosis and psoriasis. Among others, the role of apoE in modulating inflammation and oxidation is crucial in elucidating the risk factors of the above diseases since the function of apoE is closely linked with both proinflammatory and antiinflammatory cytokines. Moreover, apoE modulates inflammatory and immune responses in an isoform-dependent manner. Correspondingly, inflammatory cytokines can either upregulate or downregulate the production of apoE in various tissue types. However, studies on the interactions between apoE and cytokines occasionally yield conflicting results, highlighting the complex roles of apoE and cytokines in various disorders. The present paper summarizes the current knowledge about the cross-talk between apoE and cytokines, with emphasis on the effects of apoE on the Th1/Th2 balance.
    Mediators of Inflammation 06/2011; 2011(4852):949072. DOI:10.1155/2011/949072 · 3.24 Impact Factor
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    • "Contrary to published evidence documenting the protective effects of apoE, our laboratory found that injections of apoE increased CLP-induced septic morbidity and mortality in a dose-dependent manner [88]. This discrepancy between the literature and our findings could be attributed to differences in the experimental models, since the predominant model is a single injection of one type of endotoxin and a single dose of apoE, whereas our model uses continuous release of various types of fecal bacteria and four consecutive doses of apoE. "
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    ABSTRACT: 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 proinflammatory cascades that include the activation of various immune cells and the exuberant secretion of proinflammatory cytokines by these cells. Natural killer T-cells (NKTs) are a sublineage 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.
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