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Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways

Abstract

Atherosclerosis, the leading cause of death in developed countries, has been linked to hypercholesterolemia for decades. More recently, atherosclerotic lesion progression has been shown to depend on persistent, chronic inflammation in the artery wall1. Although several studies have implicated infectious agents in this process, the role of infection in atherosclerosis remains controversial2,3,4. Because the involvement of monocytes and macrophages in the pathogenesis of atherosclerosis is well established, we investigated the possibility that macrophage innate immunity signaling pathways normally activated by pathogens might also be activated in response to hyperlipidemia. We examined atherosclerotic lesion development in uninfected, hyperlipidemic mice lacking expression of either lipopolysaccharide (LPS) receptor CD14 or myeloid differentiation protein-88 (MyD88), which transduces cell signaling events downstream of the Toll-like receptors (TLRs), as well as receptors for interleukin-1 (IL-1) and IL-18. Whereas the MyD88-deficient mice evinced a marked reduction in early atherosclerosis, mice deficient in CD14 had no decrease in early lesion development. Inactivation of the MyD88 pathway led to a reduction in atherosclerosis through a decrease in macrophage recruitment to the artery wall that was associated with reduced chemokine levels. These findings link elevated serum lipid levels to a proinflammatory signaling cascade that is also engaged by microbial pathogens.

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Figure 1: Deficiency of MyD88, but not of the bacterial LPS receptor CD14, markedly reduces atherosclerosis in Apoe−/− mice.
Figure 2: RNA expression profiling of mouse aortas reveals reduced chemokine expression in the absence of MyD88.
Figure 3: MCP-1 protein levels and macrophage recruitment are decreased in the absence of MyD88.

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Acknowledgements

This work was supported by National Institutes of Health grants HL66678, HL45098, RR14466 and DK50305. H.B. is supported by the Swedish Research Council. We thank X. Li for assistance with the statistical analysis and C. Chase for technical assistance with the mouse atherosclerosis studies.

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Correspondence to Mason W Freeman.

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Björkbacka, H., Kunjathoor, V., Moore, K. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 10, 416–421 (2004). https://doi.org/10.1038/nm1008

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