Chlamydia pneumoniae Infection Promotes Vascular Smooth Muscle Cell Migration through a Toll-Like Receptor 2-Related Signaling Pathway

Abstract

The migration of vascular smooth muscle cells (VSMCs) from the media to the intima is proposed to be a key event in the development of atherosclerosis. Recently, we reported that Chlamydia pneumoniae infection is involved in VSMC migration. However, the exact mechanisms for C. pneumoniae infection-induced VSMC migration are not yet well elucidated. In this study, we examined the role of the Toll-like receptor 2 (TLR2) activation-related signaling pathway in VSMC migration induced by C. pneumoniae infection. An Affymetrix-based gene expression array was conducted to identify the changes of gene expression in rat primary VSMCs (rVSMCs) infected with C. pneumoniae. Both the microarray analysis and quantitative real-time reverse transcription (RT)-PCR revealed that TLR2 mRNA expression was strongly upregulated 12 h after C. pneumoniae infection. RT-PCR and Western blot analysis further showed that the expression levels of TLR2 mRNA and protein significantly increased at the different time points after infection. Immunocytochemical analysis suggested a TLR2 recruitment to the vicinity of C. pneumoniae inclusions. Cell migration assays showed that the TLR2-neutralizing antibody could significantly inhibit C. pneumoniae infection-induced rVSMC migration. In addition, C. pneumoniae infection stimulated Akt phosphorylation at Ser 473, which was obviously suppressed by the PI3K inhibitor LY294002, thereby inhibiting rVSMC migration caused by C. pneumoniae infection. Furthermore, both the infection-induced Akt phosphorylation and rVSMC migration were suppressed by the TLR2-neutralizing antibody. Taken together, these data suggest that C. pneumoniae infection can promote VSMC migration possibly through the TLR2-related signaling pathway.

Tollip Negatively Regulates Vascular Smooth Muscle Cell–Mediated Neointima Formation by Suppressing Akt‐Dependent Signaling

“…In the vasculature, activated TLR signaling increases VSMC phenotypic switching, proliferation, and migration, which are essential processes in neointima formation 12, 13, 27. This evidence suggests that targeting TLR signaling may be a novel therapeutic target for treating neointima formation.…”

“…Tollip can physically associate with TLR2 and TLR4 to suppress TLR signaling 11. TLR2 participates in Chlamydia pneumoniae infection–mediated VSMC migration 12. In addition, Graaf and colleagues demonstrated that heat shock protein 60–induced activation of TLR2 and TLR4 could contribute to VSMC proliferation 13.…”

TLR4 rs1927911, but Not TLR2 rs5743708, Is Associated With Atherosclerotic Cerebral Infarction in the Southern Han Population

“… 31 TLR2 and TLR4 may play a role in C pneumoniae -induced foam cell formation and VSMC migration. 32 – 34 Therefore, TLR4 and TLR2 are important candidate genes for ACI.…”

Chlamydia pneumoniae Infection and Inflammatory Diseases

“…In vitro studies demonstrate that C. pneumonia –infected rat vascular SMCs enhanced migration in a TLR2-dependent manner. 67 Rabbit-infected vascular SMCs show enhanced proliferation in response to C. pneumoniae through hsp60 and the extracellular regulated kinase-1 and −2 pathways; this is further enhanced in the presence of oxLDL. 44,51 Furthermore, in vitro studies with human vascular SMCs show that C. pneumoniae EBs induce hsp60, and this activates TLR4-mediated p44/p42 MAPK activation and SMC proliferation.…”