Modulation of atherosclerosis in mice by Toll-like receptor 2.
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.
Mullick
Adam E
AE
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA. amullick@scripps.edu
Tobias
Peter S
PS
Curtiss
Linda K
LK
D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012720:Severity of Illness Index; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D008074:Lipoproteins; D011973:Receptors, LDL; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C030104:lipoprotein cholesterol; D002784:Cholesterol