Experimental and clinical studies link Chlamydia pneumoniae infection to atherogenesis and atherothrombotic events, but the underlying mechanisms are unclear. We tested the hypothesis that C. pneumoniae-induced acceleration of atherosclerosis in apolipoprotein E (ApoE) -/- mice is reciprocally modulated by activation of TLR-mediated innate immune and liver X receptor α (LXRα) signaling pathways. We infected ApoE -/- mice and ApoE -/- mice that also lacked TLR2, TLR4, MyD88, or LXRα intranasally with C. pneumoniae followed by feeding of a high fat diet for 4 mo. Mock-infected littermates served as controls. Atherosclerosis was assessed in aortic sinuses and in en face preparation of whole aorta. The numbers of activated dendritic cells (DCs) within plaques and the serum levels of cholesterol and proinflammatory cytokines were also measured. C. pneumoniae infection markedly accelerated atherosclerosis in ApoE-deficient mice that was associated with increased numbers of activated DCs in aortic sinus plaques and higher circulating levels of MCP-1, IL-12p40, IL-6, and TNF-α. In contrast, C. pneumoniae infection had only a minimal effect on atherosclerosis, accumulation of activated DCs in the sinus plaques, or circulating cytokine increases in ApoE -/- mice that were also deficient in TLR2, TLR4, or MyD88. However, C. pneumoniae-induced acceleration of atherosclerosis in ApoE -/- mice was further enhanced in ApoE -/- LXRα -/- double knockout mice and was accompanied by higher serum levels of IL-6 and TNF-α. We conclude that C. pneumoniae infection accelerates atherosclerosis in hypercholesterolemic mice predominantly through a TLR/MyD88-dependent mechanism and that LXRα appears to reciprocally modulate and reduce the proatherogenic effects of C. pneumoniae infection. Copyright © 2008 by The American Association of Immunologists, Inc.
Naiki, Y., Sorrentino, R., Wong, M. H., Michelsen, K. S., Shimada, K., Chen, S., … Arditi, M. (2014). TLR/MyD88 and Liver X Receptor Signaling Pathways Reciprocally Control Chlamydia pneumoniae-Induced Acceleration of Atherosclerosis. The Journal of Immunology, 181(10), 7176–7185. https://doi.org/10.4049/jimmunol.181.10.7176