Lack of Interleukin-1β Decreases the Severity of Atherosclerosis in ApoE-Deficient Mice

Kirii, Hirokazu; Niwa, Toshifumi; Yamada, Yasuhiro; Wada, Hisayasu; Saito, Kuniaki; Iwakura, Yoichiro; Asano, Masahide; Moriwaki, Hisataka; Seishima, Mitsuru

doi:10.1161/01.atv.0000064374.15232.c3

Cited by 670 publications

(479 citation statements)

References 28 publications

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“…The mechanisms whereby the presence of systemic inflammation translates into increased risk for atherosclerosis are largely unknown. Inflammation in the arterial wall is recognized as a major driving force in atherogenesis, and several findings suggest that IL-1b is one of the key players in the pathogenesis of atherosclerosis (65). In this article, we showed that SAA alone is capable FIGURE 6.…”

Section: Discussionmentioning

confidence: 79%

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Niemi

Teirilä

Lappalainen

et al. 2011

The Journal of Immunology

243

225

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Serum amyloid A (SAA) is an acute-phase protein, the serum levels of which can increase up to 1000-fold during inflammation. SAA has a pathogenic role in amyloid A-type amyloidosis, and increased serum levels of SAA correlate with the risk for cardiovascular diseases. IL-1β is a key proinflammatory cytokine, and its secretion is strictly controlled by the inflammasomes. We studied the role of SAA in the regulation of IL-1β production and activation of the inflammasome cascade in human and mouse macrophages, as well as in THP-1 cells. SAA could provide a signal for the induction of pro–IL-1β expression and for inflammasome activation, resulting in secretion of mature IL-1β. Blocking TLR2 and TLR4 attenuated SAA-induced expression of IL1B, whereas inhibition of caspase-1 and the ATP receptor P2X7 abrogated the release of mature IL-1β. NLRP3 inflammasome consists of the NLRP3 receptor and the adaptor protein apoptosis-associated speck-like protein containing CARD (a caspase-recruitment domain) (ASC). SAA-mediated IL-1β secretion was markedly reduced in ASC−/− macrophages, and silencing NLRP3 decreased IL-1β secretion, confirming NLRP3 as the SAA-responsive inflammasome. Inflammasome activation was dependent on cathepsin B activity, but it was not associated with lysosomal destabilization. SAA also induced secretion of cathepsin B and ASC. In conclusion, SAA can induce the expression of pro–IL-1β and activation of the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. Thus, during systemic inflammation, SAA may promote the production of IL-1β in tissues. Furthermore, the SAA-induced secretion of active cathepsin B may lead to extracellular processing of SAA and, thus, potentially to the development of amyloid A amyloidosis.

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Section: Discussionmentioning

confidence: 79%

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Niemi

Teirilä

Lappalainen

et al. 2011

The Journal of Immunology

243

225

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“…Thus, the aortic mRNA expression of VCAM-1 is increased in lesioned aortas of hypercholesterolemic rabbits, LDL-receptor-deficient mice and apo-EϪ/Ϫ mice compared with control animals (32). This finding may to some extent reflect the modulatory effect of monocytes/macrophages and lymphocytes within the developing lesions (46).…”

Section: Discussionmentioning

confidence: 87%

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Bro¹,

Moeller²,

Andersen

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Chronic renal failure markedly accelerates atherosclerosis in apolipoprotein-E-deficient mice, but the mechanism is unknown. The recruitment of inflammatory cells in the arterial wall by vascular adhesion molecules plays a key role in the formation of classical atherosclerosis. This study examines whether the expression of vascular adhesion molecules is increased in uremic atherosclerosis. Uremia was induced by 5/6 nephrectomy; control mice were sham-operated. After 2 wk of uremia, no lesion formation could be demonstrated in uremic or control mice. After 12 wk, aortas from uremic mice had a 9.8-fold increase of the aortic plaque area fraction compared with control mice (P Ͻ 0.0001). The aortic expression of intercellular adhesion molecule-1 (ICAM-1) mRNA in uremic mice was 215 Ϯ 31% (P Ͻ 0.05) and 243 Ϯ 55% (P Ͻ 0.05) of that in controls after 2 and 12 wk, respectively (n ϭ 9 ϫ 4). In contrast, aortic expression of vascular cell adhesion molecule-1 (VCAM-1) mRNA in uremic mice was unchanged after 2 wk but increased to 237 Ϯ 40% (P Ͻ 0.01) of that in control mice after 12 wk. On immunohistochemistry of aortas from uremic mice, ICAM-1 was predominantly present in endothelial cells both in nonlesioned and lesioned aortas, whereas VCAM-1 was predominantly present in the medial smooth muscle cell layer in lesioned aortas. The plasma concentration of soluble ICAM-1 (sICAM-1) (but not of sVCAM-1) was slightly elevated after 2 wk of uremia. In contrast, both sICAM-1 and sVCAM-1 plasma concentrations were markedly higher in uremic than control mice after 12 wk. These results suggest that uremic atherosclerosis is preceded by an upregulation of ICAM-1 expression in arterial endothelium and that formation of early uremic lesions is accompanied by upregulation of VCAM-1 expression in the medial smooth muscle cell layer.

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“…7,18 Studies have attempted to reduce the level or action of cytokines such as IL-1, which has been shown to recruit and stimulate cells into the inflammatory process. 27 Recently, Kirii et al 41 recently showed that, in ApoE Ϫ/Ϫ mice, genetic ablation of IL-1␤ reduced atherosclerosis by only 30%, perhaps because of persistent IL-1␣ stimulation of the IL-1R or because of alternative pathways. To establish a causative role for bacteria-enhanced atherosclerosis and dissect the inflammatory pathway, we have used our murine model (ApoE ϩ/Ϫ ) genetically deficient in IL-1R1 signaling.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1 Receptor Signaling Mediates Atherosclerosis Associated With Bacterial Exposure and/or a High-Fat Diet in a Murine Apolipoprotein E Heterozygote Model

et al. 2004

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Background— Current data demonstrate that progressive atherosclerosis is associated with activation of the inflammatory process, as evidenced by systemic elevations of molecules such as tumor necrosis factor, interleukin (IL)-6, and IL-1. It has been postulated that inflammatory events within an atherogenic lesion are induced by oxidized LDL. Recent evidence suggests that infectious agents, including those that cause periodontal disease, may also play an important role. Studies presented here tested the hypothesis that IL-1 receptor (IL-1R1) signaling plays a crucial role in bacteria- and/or high-fat diet (HFD)–enhanced atherogenesis. Methods and Results— Ten-week-old ApoE +/− mice lacking either 1 IL-1R1 allele (ApoE +/− /IL-1R1 +/− ) or 2 IL-1R1 alleles (ApoE +/− /IL-1R1 −/− ) fed either an HFD or regular chow were inoculated intravenously with live Porphyromonas gingivalis ( P gingivalis ) (10 7 CFU), an important periodontal pathogen, or vehicle once per week for 14 or 24 consecutive weeks. Histomorphometry of plaque cross-sectional area in the proximal aortas, en face measurement of plaque area over the aortic trees, and ELISA for systemic proinflammatory mediators were performed. Atherosclerotic lesions of proximal aortas and aortic tree were substantially reduced in ApoE +/− /IL-1R1 −/− mice than in ApoE +/− /IL-1R1 +/− mice challenged with P gingivalis. At 24 weeks after P gingivalis inoculation, proximal aortic lesion size quantified by histomorphometry was 5-fold–reduced in chow-fed ApoE +/− /IL-1R1 −/− mice than in ApoE +/− /IL-1R1 +/− mice ( P <0.05). In the HFD group, ApoE +/− /IL-1R1 −/− mice exhibited marked attenuation of the progression of atherosclerotic lesions (78% to 97%), with and without P gingivalis inoculation ( P <0.05) Conclusion— Ablation of IL-1R1 under P gingivalis challenge and/or an HFD reduced the progression of atherosclerotic plaques. These results indicate that IL-1 plays a crucial role in bacteria- and/or HFD-enhanced atherogenesis.

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Lack of Interleukin-1β Decreases the Severity of Atherosclerosis in ApoE-Deficient Mice

Cited by 670 publications

References 28 publications

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Serum Amyloid A Activates the NLRP3 Inflammasome via P2X7 Receptor and a Cathepsin B-Sensitive Pathway

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

Interleukin-1 Receptor Signaling Mediates Atherosclerosis Associated With Bacterial Exposure and/or a High-Fat Diet in a Murine Apolipoprotein E Heterozygote Model

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