Objective: Inflammatory cell activation plays a key role in atherosclerotic plaque growth and acute complications. While secretion of proteases and inflammatory cytokines are likely involved in the development of plaque instability, the precise mechanistic pathways are not well understood.
Methods and results: Based on our previous study, we crossed Toll-like receptor 3 (Tlr3)(-/-) mice with a unique BALB-Apoe(-/-)Npc1(-/-) plaque complication-susceptible mouse model, as well as the widely-used B6-Ldlr(-/-) atherosclerosis model, to test the role of TLR3 signaling in the development of plaque instability. TLR3-deficient mice showed no change in aortic root lesion area, but displayed a marked increase in collagen and smooth muscle cell (SMC) content of lesions. Notably, Apoe(-/-)Npc1(-/-)Tlr3(-/-) mice exhibited a 50% reduction in the incidence of medial destruction, a precursor to aortic aneurysm formation. MMP-2 activity was markedly reduced in aortic extracts from Apoe(-/-)Npc1(-/-)Tlr3(-/-) compared to controls, while both MMP-2 and -9 activities were reduced in Ldlr(-/-)Tlr3(-/-) extracts. Consistent with the in vivo data, TLR3 deficiency suppressed MMP-2 activity induced by TNF-α or polyinosine-polycytidylic acid in macrophages from Apoe(-/-)Npc1(-/-) mice.
Conclusions: TLR3 plays a critical role in regulating the degradation of extracellular matrix in lesions, in part by modulation of macrophage MMP-2 and -9 activities.
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