Chlamydia pneumoniae-Induced Macrophage Foam Cell Formation Is Mediated by Toll-Like Receptor 2

Chlamydia pneumoniae induces macrophage foam cell formation, a hallmark of early atherosclerosis, in the presence of low-density lipoprotein (LDL). This study examined the role that Toll-like receptor 2 (TLR2) and TLR4 may play in pathogen-induced foam cell formation. Murine macrophage RAW 264.7 cells either infected with C. pneumoniae or treated with the TLR4 ligand E. coli lipopolysaccharide (LPS) or the TLR2 ligand Pam3-Cys-Ala-Gly-OH (Pam) became Oil Red O-stained foam cells and showed increased cholesteryl ester (CE) content when cocultured with LDL. In macrophages from TLR2 / mice, foam cells were induced by Escherichia coli LPS but not by C. pneumoniae or Pam. Conversely, C. pneumoniae or Pam, but not E. coli LPS, induced foam cells in the TLR4-deficient GG2EE macrophage cell line, suggesting that C. pneumoniae elicits foam cell formation predominantly via TLR2. Enhancing cholesterol efflux using the liver X receptor (LXR) agonist GW3965 significantly decreased the CE content of cells exposed to each of the three TLR ligands (C. pneumoniae, Pam, and E. coli LPS). Overall, our results suggest that activation of the LXR signaling pathway may affect potentially atherogenic processes modulated by the TLR ligands. Chlamydia pneumoniae causes community-acquired pneumonia, bronchitis, and other respiratory tract diseases (21). Infection also is strongly associated with atherosclerosis and cardiovascular diseases by a variety of studies. Seroepidemiological studies have indicated that patients with coronary artery disease have higher titers of anti-C. pneumoniae antibodies compared to healthy population controls (42). Pathology studies have detected the organism within atherosclerotic lesions but not in adjacent normal tissue by immunohistochemistry, PCR, and electron microscopy (19), and the pathogen has been isolated from atherosclerotic lesions and propagated in vitro (4, 19, 27). Cell biology studies have suggested that the organism can be detected in circulating leukocytes, has the capacity to infect all atheroma cell types (13, 28, 34), and can induce the expression of inflammatory cytokines, procoagulants, matrix metalloproteinase, and adhesion molecules (8, 9, 12). Animal model studies have shown that C. pneumoniae can cause arterial inflammation in normolipidemic mice and rabbits and initiate lesion development or contribute to exacerbation of lesions in rabbits or mice, respectively (29, 33). Despite the numerous indications of C. pneumoniae’s role in atherosclerosis, human secondary prevention antibiotic treatment trials have failed to benefit heart disease patients (6, 16, 35). Although this may suggest that C. pneumoniae is not causally associated with atherosclerosis or heart disease, it is more likely that other reasons account for the lack of secondary prevention antibiotic efficacy. For example, all secondary pre