TLR2/CXCR4 coassociation facilitates<i>Chlamydia pneumoniae</i>infection-induced atherosclerosis

Abstract

<i>Chlamydia pneumoniae</i> infection could play a role in atherosclerosis. Toll-like receptor 2 (TLR2) and C-X-C motif chemokine receptor 4 (CXCR4) have been both shown to be involved in atherosclerosis. However, whether and how TLR2/CXCR4 cross talk is involved in <i>C. pneumoniae</i> infection-induced atherosclerosis remains to be determined. Our study aims to demonstrate that <i>C. pneumoniae</i> infection induced the cross talk between TLR2 and CXCR4 to mediate <i>C. pneumoniae</i> infection-induced vascular smooth muscle cell (VSMC) migration and even accelerate atherosclerosis. We first found that <i>C. pneumoniae</i> infection increased the aortic lesion size (en face), cross-sectional lesion area, and lipid content in aortic root lesion, which were both significantly reduced in apolipoprotein E-null (ApoE^-/-)TLR2^-/- or CXCR4-blocked ApoE^-/- mice and were almost reversed in CXCR4-blocked ApoE^-/-TLR2^-/- mice. Subsequently, our data showed that <i>C. pneumoniae</i> infection-induced increases in VSMC contents in the atherosclerotic lesion were remarkably suppressed in ApoE^-/-TLR2^-/- mice or CXCR4-blocked ApoE^-/- mice, and were further decreased in CXCR4-blocked ApoE^-/-TLR2^-/- mice. We then demonstrated that the increase in VSMC migratory capacity caused by <i>C. pneumoniae</i> infection was inhibited by either TLR2 or CXCR4 depletion, and downregulating both TLR2 and CXCR4 further decreased <i>C. pneumoniae</i> infection-induced VSMC migration by suppressing the infection-stimulated F-actin reorganization through the inhibition of the phosphorylation of focal adhesion kinase. Taken together, our data indicate that TLR2/CXCR4 coassociation facilitates <i>C. pneumoniae</i> infection-induced acceleration of atherosclerosis by inducing VSMC migration via focal adhesion kinase-mediated F-actin reorganization.<b>NEW & NOTEWORTHY</b> Toll-like receptor 2 (TLR2) and C-X-C motif chemokine receptor 4 (CXCR4) have both been shown to be involved in atherosclerosis. We demonstrate for the first time the presence of TLR2/CXCR4 coassociation during <i>Chlamydia pneumoniae</i> infection-induced atherosclerosis. Amazingly, blocking of both TLR2 and CXCR4 significantly retards and even almost reverses this infection-induced atherosclerosis. Our work reveals new mechanisms about <i>C. pneumoniae</i> infection-induced atherosclerosis and identifies potential new therapeutic targets for the prevention and treatment of atherosclerosis.