Article

LOX-1 Deletion Improves Neutrophil Responses, Enhances Bacterial Clearance, and Reduces Lung Injury in a Murine Polymicrobial Sepsis Model

Texas Lung Injury Institute, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Texas 75708, USA.
Infection and immunity (Impact Factor: 3.73). 07/2011; 79(7):2865-70. DOI: 10.1128/IAI.01317-10
Source: PubMed

ABSTRACT

Inflammatory tissue injury and immunosuppression are the major causes of death in sepsis. Novel therapeutic targets that can
prevent excessive inflammation and improve immune responses during sepsis could be critical for treatment of this devastating
disease. LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a membrane protein expressed in endothelial cells,
has been known to mediate vascular inflammation. In the present study, we demonstrated that LOX-1 deletion markedly improved
the survival rate in a murine model of polymicrobial sepsis. Wild-type (LOX-1+/+) and LOX-1 knockout (LOX-1−/−) mice were subjected to cecal ligation and puncture (CLP) to induce sepsis. LOX-1 deletion significantly reduced systemic
inflammation and inflammatory lung injury during sepsis, together with decreased production of proinflammatory cytokines and
reduced lung edema formation. Furthermore, LOX-1 deletion improved host immune responses after the induction of sepsis, as
indicated by enhanced bacterial clearance. Interestingly, we were able to demonstrate that LOX-1 is expressed in neutrophils.
LOX-1 deletion prevented neutrophil overreaction and increased neutrophil recruitment to infection sites after sepsis induction,
contributing at least partly to increased immune responses in LOX-1 knockout mice. Our study results indicate that LOX-1 is
an important mediator of inflammation and neutrophil dysfunction in sepsis.

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Available from: Hong-Long Ji, Feb 17, 2014
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    • "b Expression levels of the inflammatory genes, including TNF-α, IL-6, and IL-1β, were measured by real-time PCR in the aortic arch isolated from mice; Control, normal chow-fed group; PBS, HFD-fed and PBS-treated group; MED, HFD-fed and MED treated group. Data indicate means ± S.D; n = 5 per group; **p < 0.01, *p < 0.05 inflammation[37]. Macrophages produce abundant amounts of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, to promote atherosclerosis. "
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    ABSTRACT: Background Mycoepoxydiene (MED) is a polyketide that can be isolated from a marine fungus and is associated with various activities, including antitumor and anti-inflammatory functions. However, its effects on atherosclerosis remain unknown. Macrophage-derived foam cells play crucial roles in the initiation and progression of atherosclerotic plaques. In this study, we investigated the effects of MED on oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation and activation, and on high fat diet (HFD)-induced atherosclerosis in ApoE-deficient (ApoE−/−) mice. Results Our findings show that MED could significantly inhibit ox-LDL-induced macrophage foam cell formation and suppress the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which is a receptor for ox-LDL. Additionally, MED could significantly inhibit the secretion of proinflammatory cytokines, such as tumor necrosis factor (TNF-α), interleukin (IL)-6, and IL-1β. Mechanistically, MED inhibited NF-κB activation by blocking IκB-α degradation and reducing NF-κB DNA binding activity. Moreover, MED dramatically reduced the occurrence of HFD-induced atherosclerotic lesions in ApoE−/− mice. Conclusions Our study shows that MED can inhibit macrophage foam cell formation and activation by inhibiting NF-κB activation, thereby protecting ApoE−/− mice from HFD-induced atherosclerosis. Our findings suggest that MED might be a potential lead compound for the development of antiatherosclerotic therapeutics. Electronic supplementary material The online version of this article (doi:10.1186/s13578-015-0017-y) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2015 · Cell and Bioscience
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    • "Obviously, TRAIL enhances infection control in this phase of sepsis through yet unknown mechanisms. As hyperinflammation increases, the termination of inflammation becomes more and more important [19]. In this stage of sepsis, neutrophils presumably become TRAIL-sensitive. "
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    ABSTRACT: TNF-related apoptosis inducing ligand (TRAIL) influences several inflammatory reactions by partially still unknown mechanisms. TRAIL is produced and expressed by several cells of the immune system. Murine Colon Ascendens Stent Peritonitis (CASP) represents a hyperinflammatory model of diffuse peritonitis. As we have shown previously, TRAIL strongly improves survival in murine CASP. This is accompanied by a significantly reduced infiltration of neutrophils in the associated lymphoid tissue. Additionally, it is known that TRAIL induces apoptosis in neutrophils and acceleration of neutrophil apoptosis enhances resolution of inflammatory reactions. In this study, we investigated the correlation of the protective effect of TRAIL in sepsis and its influence on neutrophils. We found that neutrophils infiltrating the lymphoid organs express the TRAIL-receptor DR5 at high density. Furthermore, we demonstrated that TRAIL-treatment enhances apoptosis of neutrophils in the spleen, lung and liver and decreases organ injury during sepsis. To further examine a role for neutrophils in TRAIL-mediated protection in CASP, we have depleted neutrophils 24 hours prior to CASP. In these depleted mice, administration of TRAIL was ineffective. We conclude that TRAIL induces apoptosis in tissue-infiltrating neutrophils thereby protecting organs from sepsis-induced injury.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "As a scavenger receptor, LOX-1 also binds to C-reactive protein [5], heat shock proteins [6], apoptotic cells [7], platelets [8], and bacteria [9]. LOX-1 has been associated with not only atherosclerotic disease [4] but also Alzheimer's disease [10] [11] and sepsis [12]. Because of the multifunctional properties of LOX-1, it has been considered an attractive therapeutic target for treating a variety of diseases [13] [14] [15] [16]. "
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    ABSTRACT: LOX-1physically interacts with CCT1 by pull down (View interaction) LOX-1physically interacts with CCT1 by anti bait coimmunoprecipitation (View interaction) LOX-1, M6PR1 and CCT1colocalize by fluorescence microscopy (View interaction) LOX-1physically interacts with CCT1, CCT3, CCT7, CCT5, CCT4 and CCT6A by pull down (View interaction) CCT1, LOX-1 and EEA1 colocalize by fluorescence microscopy (View interaction) CCT1 and LOX-1 colocalize by fluorescence microscopy (View interaction) LOX-1 physically interacts with CCT4 by anti bait coimmunoprecipitation (View interaction) LOX-1 binds to CCT1 by pull down (View interaction) LOX-1 binds to CCT4 by pull down (View interaction)
    Full-text · Article · Jan 2014
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