Mast cells induce vascular smooth muscle cell apoptosis via a toll-like receptor 4 activation pathway.

OBJECTIVE: Activated mast cells (MCs) release chymase, which can induce vascular smooth muscle cell (VSMC) apoptosis leading to plaque destabilization. Because the mechanism through which MCs release chymase in atherosclerosis is unknown, we studied whether MC-associated VSMC apoptosis is regulated by toll-like receptor 4 (TLR4) signaling. METHODS AND RESULTS: Local recruitment and activation of MCs reduced VSMC content specifically in the cap region of vulnerable plaques in apolipoprotein E knockout mice. Cotreatment with the TLR4 antagonist Bartonella quintana lipopolysaccharide prevented this VSMC loss, suggesting an important role for TLR4 signaling in MC-induced VSMC apoptosis. Coculture of VSMCs with MCs activated by the TLR4 agonist Escherichia coli lipopolysaccharide increased VSMC apoptosis. Apoptosis was inhibited by TLR4 and chymase blockers, indicating that TLR4 signaling is involved in chymase release in MCs. This pathway was mediated via interleukin-6 because interleukin-6 promoted MC-associated VSMC apoptosis, which was inhibited by blocking chymase release. In addition, TLR4 activation in MCs induced interleukin-6 production, which was reduced by preincubation with either B. quintana lipopolysaccharide or an anti-TLR4 antibody. CONCLUSIONS: We show that MCs promote VSMC apoptosis in vivo. In addition, TLR4 signaling is important in chymase release in MCs and, therefore, in plaque destabilization by regulating VSMC apoptosis.