Abstract 126: Chlamydia Pneumoniae Induces Foam Cell Formation Of Macrophages By Activating The TLR4/TRIF/IRF3 Pathway

Abstract

Background: Chlamydia pneumoniae (CP) induces macrophage foam cell formation (FCF), a key event in early atherosclerosis, in the presence of low-density lipoprotein (LDL). Recent studies have indicated the role of Toll-Like Receptors in atherogenesis. Liver X receptors (LXR) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism and determinants of atherosclerosis. Induction of LXR-activated genes has also been shown to influence the pathogen pattern recognition activity of the Toll-like receptors 3 and 4 (TLR3/4). The TLR and the LXR pathways converge on the transcription factor IRF3. Objective: We hypothesized that TLR and the LXR and IRF3 pathways participate in CP infection mediated FCF and acceleration of atherosclerosis, and that the MyD88- independent pathway via TLR4/TRIF and IRF3 play a role in this acceleration. Methods: Peritoneal macrophages were isolated from C57BL/6 wild type (WT) mice, IRF3 −/− mice, TLR4 −/− mice and TRIF −/− mice. Cells were treated with UV killed CP (UVCP, 5x10 5 IFU) with or without ox-LDL (100 μg/ml) in the presence or absence of LXR agonist GW3965 (2nM). LPS (10 ng/ml) and PolyI:C (1μg/ml) were used as positive controls as TLR4 and TLR3 ligands, respectively. FCF was examined by Oil Red O staining. The percentages of foam cells in total macrophages were quantified. Results : FCF was significantly reduced in IRF3−/− cells compared with WT cells stimulated with UVCP plus ox-LDL. Foam cells induced by LPS with ox-LDL were also significantly reduced in IRF3−/− cells compared to WT cells (p<0.05). Furthermore, the synthetic LXR agonist GW3965 significantly diminished CP induced FCF in WT cells. FCF was significantly reduced in TLR4−/− and TRIF−/− macrophages compared to WT cells when stimulated with UVCP with ox-LDL (p<0.05). Conclusion : Chlamydia pneumoniae infection can activate the TLR4/TRIF/IRF3 pathway and does play an important role in CP- mediated foam cell formation in macrophages. Therefore, infections such as the one caused by CP, can trigger the TLR4/TRIF/IRF3 pathway leading to the down regulation of LXRs and shifting of cholesterol transport toward pro-foam cell production and thereby accelerating atherogenesis.. Supported by NIH grants AI 067995 and HL66436 to MA.