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


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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    • "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.
    PLoS ONE 06/2014; 9(6):e97451. DOI:10.1371/journal.pone.0097451 · 3.23 Impact Factor
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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)
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    • "mice were also able to clear the bacteria from peritoneum, blood, and lungs more than wild mice [10]. The contribution of LOX-1 in the development of lung tissue damage in sepsis was also observed in other models of sepsis. "
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    ABSTRACT: Oxidized low-density lipoproteins (oxLDL) and the lectin-like oxLDL receptor-1 (LOX-1) are upregulated in inflammation. Because of the importance of inflammation and capillary leakage in the impairment of the microcirculation, which in turn contributes to the development of sepsis and multiorgan failure, the role of oxidized LDL and LOX-1 as players of intestinal inflammation is of great interest. In fact, the blockade of LOX-1 during experimental endotoxemia was effective in reducing leukocyte activation. There are several mechanisms by which oxLDL can participate in local and systemic inflammation, including cell proliferation, apoptosis, capillary perfusion, leukocyte-endothelial cell interactions, and endothelial activation. This review highlights the evidence relating oxLDL and LOX-1 to proinflammatory disease mechanisms. We also indicate situations when oxLDL, because of exposure time, dose, or degree of oxidization, is involved in disease resolution. Modulation of LOX-1 response could be utilized for the treatment of local and systemic inflammation, but the successful use of this target requires further understanding of its broad effects.
    Mediators of Inflammation 08/2013; 2013(10):761789. DOI:10.1155/2013/761789 · 3.24 Impact Factor
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