Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

Wang, Yuehai; Lu, Huixia; Huang, Zhiheng; Lin, Haiyan; Lei, Zhenmin; Chen, Xiaoqing; Tang, Mengxiong; Gao, Fei; Dong, Mei; Li, Rongda; Lin, Ling

doi:10.1016/j.bbrc.2014.06.060

Cited by 17 publications

(8 citation statements)

References 20 publications

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“…Analysis of plasma from both strains with autoantigen arrays revealed continued divergence in immune activity. APOE cKO mice largely upregulated antibody responses to autoantigens at week 4 of HFD, consistent with the known role of APOE repressing immune activation 18,25,27 . In contrast, D374Y displayed significant down-regulation of multiple autoreactive IgM, whereas only 3 IgG responses were affected (Fig7e).…”

Section: Convergence Of the Aortic Response During Atherosclerosis Prsupporting

confidence: 73%

Alternate models of acute dyslipidemia reveal divergent pathways upon atherosclerosis initiation

Hellberg

Shavva

Metso

et al. 2020

Preprint

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Atherosclerosis is thought to be initiated by the sub-intimal retention of apolipoprotein-B containing lipoproteins within susceptible sites of the vasculature. Understanding this initiation is not possible with current legacy mouse models of atherosclerosis. We created two mouse strains of inducible hypercholesterolemia based on conditional loss of apolipoprotein E or through inducible expression of a gain-of-function proprotein convertase subtilisin/kexin type 9 D374Y mutation. Both strains rapidly broke plasma-lipid homeostasis and converted to a state of atherogenic dyslipidemia, resulting in overt aortic-accumulation of lipoproteins within 10 days. RNA-sequencing revealed that the vascular response is completely dependent on the route taken to dyslipidemia, which nevertheless implicates known pathogenic pathways in the aetiology of atherosclerosis, and further implicates APOE as an inhibitor of inflammation. As atherosclerosis develops, a convergence of common mechanistic processes emerge in both strains with significant involvement of the immune system, and targeting of CD8 T cells can regulate a conserved aortic response. Our results define atherosclerosis initiation as highly heterogeneous process and identify multiple potential therapeutic targets that may influence disease onset.

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Section: Convergence Of the Aortic Response During Atherosclerosis Prsupporting

confidence: 73%

Alternate models of acute dyslipidemia reveal divergent pathways upon atherosclerosis initiation

Hellberg

Shavva

Metso

et al. 2020

Preprint

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“…Furthermore, pristane-treated ApoE -/-mice also exhibited the traits of SLE, accompanied by increased serum ANA and ENA levels. Although ApoE -/-mice may spontaneously develop ANA, as reported previously (Wang et al, 2012(Wang et al, , 2014, pristane treatment resulted in a remarkable change of the ANA nuclear patterns, and the mice developed anti-Sm, anti-nRNP, and anti-ribosomal antibodies. The lupus-specific anti-Sm antibody and anti-ribosomal antibodies were found only in the ApoE -/-mice treated with pristane, not in those treated with PBS.…”

Section: Discussionmentioning

confidence: 92%

Vulnerability of atherosclerotic plaques is associated with type I interferon in a murine model of lupus and atherosclerosis

Zhang¹,

Qu²,

Ye³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. This study aimed to investigate the relationship between type I interferon (IFN-I) and plaque stability in pristane-treated apolipoprotein E-knockout (ApoE -/-) mice. Antinuclear antibody (ANA) and extractable nuclear antigen antibody (ENA) levels were measured by immunofluorescence and enzyme-linked immunospot assay. Atherosclerotic plaques were detected by Sirius red/fast green staining. Cell apoptosis was detected by terminal deoxynucleotidyltransferasemediated dUTP-biotin nick-end labeling. Gene expression was determined by real-time PCR analyses. We found that pristane-treated ApoE -/-mice developed a lupus-like syndrome characterized by an increased production of serum ANA and ENA. Pristane treatment decreased the collagen content and increased the number of apoptotic cells in plaques. Moreover, IFN-induced ISG15, IFIT1-1, and IFIT1-2 gene expression was increased in peripheral blood cells and aortic plaques. An IFN-a-stimulated macrophage supernatant inhibited collagen type I, alpha 1 gene expression in vascular smooth muscle cells. We concluded that the vulnerability of plaques was associated C.Y. Zhang et al. 14872©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 14871-14881 (2015) with the activation of IFN-I in pristane-treated ApoE -/-mice. Thus, we speculated that the higher prevalence of cardiovascular events in patients with systemic lupus erythematosus could be due to plaque instability.

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“…Apoe −/− mice show increased plasma autoantibodies to dsDNA and accelerated glomerulonephritis when crossed with gld mice, or simply in response to feeding a high-cholesterol diet. This was attributed to decreased apoptotic cell clearance (Aprahamian et al, 2004; Wang et al, 2014). Apoa1 and Apoe deficiency decrease plasma HDL levels in mice, potentially leading to DC inflammasome activation and enhanced cytokine secretion that activate T-cells, as suggested by our study.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity

et al. 2017

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Summary Autoimmune diseases such as systemic lupus erythematosus (SLE) are associated with increased cardiovascular disease and reduced plasma high-density lipoproteins (HDL) levels. HDL mediates cholesterol efflux from immune cells via the ATP Binding Cassette Transporters A1 and G1 (ABCA1/G1). The significance of impaired cholesterol efflux pathways in autoimmunity is unknown. We observed that Abca1/g1 deficient mice develop enlarged lymph nodes (LNs) and glomerulonephritis suggestive of SLE. This lupus-like phenotype was recapitulated in mice with knockouts of Abca1/g1 in dendritic cells (DCs) but not in macrophages or T-cells. DC-Abca1/g1 deficiency increased LN and splenic CD11b+ DCs, which displayed cholesterol accumulation and inflammasome activation, increased cell surface levels of the GM-CSF receptor, and enhanced inflammatory cytokine secretion. Consequently, DC-Abca1/g1 deficiency enhanced T-cell activation, Th1 and Th17-cell polarization. NLRP3 inflammasome deficiency diminished the enlarged LNs and enhanced Th1-cell polarization. These findings identify an essential role of DC cholesterol efflux pathways in maintaining immune tolerance.

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Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

Abstract: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta.

Cited by 17 publications

References 20 publications

Alternate models of acute dyslipidemia reveal divergent pathways upon atherosclerosis initiation

Alternate models of acute dyslipidemia reveal divergent pathways upon atherosclerosis initiation

Vulnerability of atherosclerotic plaques is associated with type I interferon in a murine model of lupus and atherosclerosis

Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity

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Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

Abstract: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta.

Cited by 17 publications

References 20 publications

Alternate models of acute dyslipidemia reveal divergent pathways upon atherosclerosis initiation

Alternate models of acute dyslipidemia reveal divergent pathways upon atherosclerosis initiation

Vulnerability of atherosclerotic plaques is as­sociated with type I interferon in a murine model of lupus and atherosclerosis

Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity

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Vulnerability of atherosclerotic plaques is associated with type I interferon in a murine model of lupus and atherosclerosis