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

Sep 9, 2004Circulation

Inflammation signaling may link artery plaque buildup to bacterial exposure and high-fat diet in mice with genetic risk: treatment insights

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Abstract

Proximal aortic lesion size was 5-fold reduced in mice lacking IL-1 receptor signaling when challenged with the periodontal pathogen Porphyromonas gingivalis.

Atherosclerotic lesions were significantly smaller in mice lacking one or two IL-1 receptor alleles compared to those with a single allele when exposed to P gingivalis.
In a high-fat diet group, lesion progression was reduced by 78% to 97% in mice without IL-1 receptors, regardless of P gingivalis inoculation.
Systemic proinflammatory mediators were measured, indicating a relationship between IL-1 signaling and inflammation in atherosclerosis.
The findings suggest that IL-1 receptor signaling is associated with enhanced atherogenesis due to bacterial challenge and high-fat diet.

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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).

CONCLUSIONS: 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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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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