Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection

Bont, N. de; Netea, Mihai G.; Demacker, P.N.M.; Dijk, Ko Willems van; Kullberg, Bart‐Jan; Meer, J.W.M. van der; Stalenhoef, A.F.H.

doi:10.1016/s0021-9150(99)80362-1

Cited by 91 publications

(120 citation statements)

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“…In contrast to the enhanced TNF production in hypercholesterolemic mice after infection with bacteria (8,9) or C. albicans (10), TNF concentrations in serum of LCMV-infected normo-and hypercholesterolemic mice were below the limits of detection (Ͻ5 pg/ml; data not shown). This suggested that excessive TNF production in hypercholesterolemic mice is unlikely to contribute importantly to the exacerbated virus-induced immunopathology.…”

Section: Impaired Virus Clearance In Hypercholesterolemic Micementioning

confidence: 73%

“…Successful immune responses against fast replicating, cytopathic infectious agents depend mainly on innate immune mechanisms, such as type I IFN (29), or complement (44,45). The high susceptibility of LDLR Ϫ/Ϫ mice to generalized Candidiasis (10) and of ApoE Ϫ/Ϫ mice to L. monocytogenes (8) and Klebsiella infection (9) suggests that hypercholesterolemia leads to an impairment of innate immune responses. In noncytopathic LCMV infection, innate immune responses contribute to limit the initial spread of the virus and therefore limit or prevent immunopathologic disease or exhaustion (46).…”

Section: Discussionmentioning

confidence: 99%

“…First, nonspecific resistance and specific immune responses in hypercholesterolemic mice might be increased, leading to a more vigorous antiviral response with more "bystander" damage. In particular, TNF, which has been shown to be up-regulated after infection of hypercholesterolemic mice with bacteria (8,9) or C. albicans (10), may mediate such pathological effects. To address this first possibility, serum TNF values were determined after infection with 200 PFU of LCMV in ApoE Ϫ/Ϫ , LDLR…”

Section: Impaired Virus Clearance In Hypercholesterolemic Micementioning

confidence: 99%

“…However, high lipoprotein levels in plasma diminish systemic cytokine responses (6,7). Furthermore, high plasma cholesterol levels can result in impaired antibacterial immune responses, as shown by the failure of genetically hypercholesterolemic apolipoprotein E (ApoE) 3 -deficient (ApoE Ϫ/Ϫ ) mice to rapidly clear Listeria monocytogenes (8) or Klebsiella pneumoniae infection (9). Similarly, hypercholesterolemic mice lacking the low density lipoprotein receptor (LDLR Ϫ/Ϫ ) are highly susceptible to disseminated Candida albicans infection (10).…”

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confidence: 99%

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Hypercholesterolemia Exacerbates Virus-Induced Immunopathologic Liver Disease Via Suppression of Antiviral Cytotoxic T Cell Responses

Ludewig

Jäggi

Dumrese

et al. 2001

The Journal of Immunology

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The immune system has to be optimally balanced to be highly effective against infections with cytopathic microbial pathogens and must guarantee efficient destruction of cells infected with noncytopathic agents while leaving the integrity of noninfected cells largely unaltered. We describe here the effects of genetically induced hypercholesterolemia on cellular immunity in apolipoprotein E (ApoE−/−) and low density lipoprotein receptor-deficient (LDLR−/−) mice during infection with the hepatotropic lymphocytic choriomeningitis virus WE strain. In both ApoE−/− and LDLR−/− mice hypercholesterolemia aggravated virus-induced immunopathologic liver disease. ApoE−/− mice exhibited a higher susceptibility to virus-induced immunopathology than LDLR−/− mice and usually succumbed to immunopathologic disease when infected with high doses of virus. Initial virus spread was not influenced by the hypercholesterolemia, whereas clearance of the virus from spleen and nonlymphoid organs, including liver, was delayed. Activation of antiviral CTL, measured by ex vivo cytotoxicity and IFN-γ production, and recruitment of specific CTL into blood and liver were impaired in hypercholesterolemic mice, indicating that hypercholesterolemia had a significant suppressive effect on cellular immunity. Taken together, these data provide evidence that hypercholesterolemia suppresses antiviral immune responses, thereby changing the host-virus balance, and can increase susceptibility to acute or chronic and potentially lethal virus-induced immunopathologic disease. These findings impinge on our understanding of hypercholesterolemia as a disease parameter and may explain aspects of the frequent association of persistent pathogens with hypercholesterolemia-induced diseases, such as atherosclerosis.

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Section: Impaired Virus Clearance In Hypercholesterolemic Micementioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Impaired Virus Clearance In Hypercholesterolemic Micementioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Hypercholesterolemia Exacerbates Virus-Induced Immunopathologic Liver Disease Via Suppression of Antiviral Cytotoxic T Cell Responses

Ludewig

Jäggi

Dumrese

et al. 2001

The Journal of Immunology

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“…In addition to cholesterol transport, apoE has significant immunomodulatory properties, including the capacity to suppress lymphocyte proliferation, Ig synthesis, and neutrophil activation (4-7). These immunomodulatory properties appear to be biologically relevant, because apoEdeficient animals have impaired immunity after exposure to Listeria monocytogenes and are more susceptible to endotoxemia after inoculation with LPS or Klebsiella pneumonia (8,9). ApoEdeficient mice, compared with wild-type mice, show differences in delayed-type hypersensitivity and IgM responses to Ag (10).…”

mentioning

confidence: 99%

Apolipoprotein E and Peptide Mimetics Modulate Inflammation by Binding the SET Protein and Activating Protein Phosphatase 2A

Christensen

Ohkubo

Oddo

et al. 2011

The Journal of Immunology

109

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The molecular mechanism by which apolipoprotein E (apoE) suppresses inflammatory cytokine and NO production is unknown. Using an affinity purification approach, we found that peptide mimetics of apoE, derived from its receptor binding domain residues 130–150, bound to the SET protein, which is a potent physiological inhibitor of protein phosphatase 2A (PP2A). Both holo-apoE protein and apoE-mimetic peptides bound to the C-terminal region of SET, which is then associated with an increase in PP2A-mediated phosphatase activity. As physiological substrates for PP2A, the LPS-induced phosphorylation status of signaling MAPK and Akt kinase is reduced following treatment with apoE-mimetic peptides. On the basis of our previous report, in which apoE-mimetic peptides reduced I-κB kinase and NF-κB activation, we also demonstrate a mechanism for reduced production of inducible NO synthase protein and its NO product. These data provide evidence for a novel molecular mechanism by which apoE and apoE-mimetic peptides antagonize SET, thereby enhancing endogenous PP2A phosphatase activity, which reduces levels of phosphorylated kinases, signaling, and inflammatory response.

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Lipophorin of lower density is formed during immune responses in the lepidopteran insect Galleria mellonella

et al. 2001

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Injection of heat-killed bacteria into larvae of the greater wax moth Galleria mellonella is followed by changes in lipoprotein composition in the hemolymph. Density gradient centrifugation experiments revealed that within the first four hours after injection, a part of larval lipoprotein, high-density lipophorin (HDLp), was converted into a lipoprotein of lower density. SDS-polyacrylamide gel electrophoresis analysis of the gradient fractions and sequencing of protein fragments, established that the exchangeable apolipoprotein apolipophorin III (apoLp-III), a potent immune-activator, was associated with this newly formed lipophorin. To investigate further the influence of lipophorin-associated apoLp-III on immune-related reactions, we performed in vitro studies with isolated hemocytes from G. mellonella and lipophorins from the sphinx moth Manduca sexta, as a natural source of high amounts of low-density lipophorin (LDLp) and HDLp. The hemocytes were activated to form superoxide radicals upon incubation with LDLp, but not with HDLp. Fluorescence-labeled LDLp was specifically taken up by granular cells. This process was inhibited by adding an excess of unlabeled LDLp, but not by HDLp. We hypothesize that larval lipophorin formed in vivo is an endogenous signal for immune activation, specifically mediated by the binding of lipid-associated apoLp-III to hemocyte membrane receptors.

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Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection

Cited by 91 publications

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Hypercholesterolemia Exacerbates Virus-Induced Immunopathologic Liver Disease Via Suppression of Antiviral Cytotoxic T Cell Responses

Hypercholesterolemia Exacerbates Virus-Induced Immunopathologic Liver Disease Via Suppression of Antiviral Cytotoxic T Cell Responses

Apolipoprotein E and Peptide Mimetics Modulate Inflammation by Binding the SET Protein and Activating Protein Phosphatase 2A

Lipophorin of lower density is formed during immune responses in the lepidopteran insect Galleria mellonella

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