Modulation of atherosclerosis in mice by Toll-like receptor 2
Adam E. Mullick, Peter S. Tobias, Linda K. Curtiss
Adam E. Mullick, Peter S. Tobias, Linda K. Curtiss
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Research Article Cardiology

Modulation of atherosclerosis in mice by Toll-like receptor 2

Abstract

Epidemiologic evidence has established a relationship between microbial infection and atherosclerosis. Mammalian TLRs provide clues on the mechanism of this inflammatory cascade. TLR2 has a large ligand repertoire that includes bacterial-derived exogenous and possibly host-derived endogenous ligands. In atherosclerosis-susceptible low-density lipoprotein receptor–deficient (Ldlr–/–) mice, complete deficiency of TLR2 led to a reduction in atherosclerosis. However, with BM transplantation, loss of TLR2 expression from BM-derived cells had no effect on disease progression. This suggested that an unknown endogenous TLR2 agonist influenced lesion progression by activating TLR2 in cells that were not of BM cell origin. Moreover, with intraperitoneal administration of a synthetic TLR2/TLR1 agonist, Pam3CSK4, disease burden was dramatically increased in Ldlr–/– mice. A complete deficiency of TLR2 in Ldlr–/– mice, as well as a deficiency of TLR2 only in BM-derived cells in Ldlr–/– mice, led to striking protection against Pam3CSK4-mediated atherosclerosis, suggesting a role for BM-derived cell expression of TLR2 in transducing the effects of an exogenous TLR2 agonist. These studies support the concept that chronic or recurrent microbial infections may contribute to atherosclerotic disease. Additionally, these data suggest the presence of host-derived endogenous TLR2 agonists.

Authors

Adam E. Mullick, Peter S. Tobias, Linda K. Curtiss

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Measurement of aortic atherosclerosis in Pam3-exposed TLR2 chimeric mice...
Measurement of aortic atherosclerosis in Pam3-exposed TLR2 chimeric mice. (A) Aortic atherosclerosis expressed as a percentage of total area after 12 weeks of an HFD and weekly i.p. injections of Pam3 in female Ldlr–/– mice that underwent BM reconstitution from Tlr+/+ or Tlr2–/– donor mice. (B–E) Representative aortae from Ldlr–/– recipient mice of the following groups: Tlr2+/+ BM donor, vehicle injection (B); Tlr2+/+ BM donor, 50 μg Pam3 per week (C); Tlr2–/– BM donor, vehicle injection (D); and Tlr2–/– BM donor, 50 μg Pam3 per week (E). Pam3 administration increased lesion severity in animals expressing TLR2 in their BM-derived cells resulting in profuse abdominal aortic atherosclerosis. Slight increases in lesion severity were observed in Tlr2–/– recipient animals receiving Pam3. Scale bar: 0.5 cm.