Chlamydia pneumoniae-induced foam cell formation requires MyD88-dependent and -independent signaling and is reciprocally modulated by liver X receptor activation.
Chlamydia pneumoniae-induced foam cell formation requires MyD88-dependent and -independent signaling and is reciprocally modulated by liver X receptor activation.
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DOI：
10.4049/jimmunol.181.10.7186
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发表时间：
2008-11-15
期刊：
影响因子：
--
通讯作者：
Arditi M
中科院分区：
文献类型：
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作者：
Chen S;Sorrentino R;Shimada K;Bulut Y;Doherty TM;Crother TR;Arditi M
肺炎衣原体由巨噬细胞和其他抗原提呈细胞通过Toll样受体(TLRs)检测，并可加剧动脉粥样硬化病变的发展，但其发生机制尚不清楚。肝X受体(LXRs)集中控制胆固醇的反向转运，但也负向调节TLR介导的炎症途径。我们分离了野生型、TLR2、TLR3、TLR4、TLR2/4、MyD88、TRIF、MyD88/TRIF和IRF3基因敲除小鼠的腹膜巨噬细胞，在存在或不存在氧化型低密度脂蛋白(ox-LDL)的情况下，用活的或紫外线灭活的肺炎衣原体处理它们，然后测定泡沫细胞的形成。在一些实验中，合成的LXR激动剂GW3965被添加到存在ox-LDL的感染肺炎链球菌的巨噬细胞中。活菌和紫外线灭活肺炎衣原体均可诱导野生型巨噬细胞IRF3激活并促进泡沫细胞的形成，而TLR2、TLR4、MyD88、TRIF或IRF3基因缺失而TLR3基因缺失可显著减少泡沫细胞的形成。LXR激动剂GW3965显著减少肺炎衣原体诱导的泡沫细胞的形成，进而抑制肺炎衣原体诱导的IRF3激活，提示存在双向串扰。我们得出结论，肺炎衣原体通过激活TLR2和TLR4信号下游的MyD88依赖和MyD88非依赖(即TRIF依赖和IRF3依赖)途径促进泡沫细胞的形成，而TLR3不参与这一过程。这一机制至少可以部分解释为什么肺炎衣原体感染会加速动脉粥样硬化斑块的形成，并支持LXR激动剂可能被证明在临床上有效地抑制动脉粥样硬化形成的观点。
Chlamydia pneumoniae is detected by macrophages and other antigen presenting cells via Toll-like receptors (TLRs), and can exacerbate developing atherosclerotic lesions, but how that occurs is not known. Liver X receptors (LXRs) centrally control reverse cholesterol transport, but also negatively modulate TLR-mediated inflammatory pathways. We isolated peritoneal macrophages from wild type, TLR2, TLR3, TLR4, TLR2/4, MyD88, TRIF, MyD88/TRIF and IRF3 knockout mice and treated them with live or UV-killed C. pneumoniae in the presence or absence of oxidized LDL (ox-LDL), then measured foam cell formation. In some experiments, the synthetic LXR agonist GW3965 was added to macrophages infected with C. pneumoniae in the presence of ox-LDL. Both live and UV-killed C. pneumoniae induced IRF3 activation and promoted foam cell formation in wild type macrophages, while the genetic absence of TLR2, TLR4, MyD88, TRIF, or IRF3 but not TLR3 significantly reduced foam cell formation. C. pneumoniae-induced foam cell formation was significantly reduced by the LXR agonist GW3965, which in turn inhibited C. pneumoniae-induced IRF3 activation, suggesting a bidirectional cross talk. We conclude that C. pneumoniae facilitates foam cell formation via activation of both MyD88-dependent and MyD88-independent (i.e. TRIF- dependent and IRF3-dependent) pathways downstream of TLR2 and TLR4 signaling, and that TLR3 is not involved in this process. This mechanism could at least partly explain why infection with C. pneumoniae accelerates development of atherosclerotic plaque, and lends support to the proposal that LXR agonists might prove clinically useful in suppressing atherogenesis.