Storage lipid studies in tuberculosis reveal that foam cell biogenesis is disease-specific.
Storage lipid studies in tuberculosis reveal that foam cell biogenesis is disease-specific.
复制标题
结核病的储存脂质研究表明，泡沫细胞的生物发生具有疾病特异性。
DOI：
10.1371/journal.ppat.1007223
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发表时间：
2018-08
期刊：
影响因子：
6.7
通讯作者：
Gennaro ML
中科院分区：
文献类型：
--
作者：
Guerrini V;Prideaux B;Blanc L;Bruiners N;Arrigucci R;Singh S;Ho-Liang HP;Salamon H;Chen PY;Lakehal K;Subbian S;O'Brien P;Via LE;Barry CE 3rd;Dartois V;Gennaro ML
Foam cells are lipid-laden macrophages that contribute to the inflammation and tissue damage associated with many chronic inflammatory disorders. Although foam cell biogenesis has been extensively studied in atherosclerosis, how these cells form during a chronic infectious disease such as tuberculosis is unknown. Here we report that, unlike the cholesterol-laden cells of atherosclerosis, foam cells in tuberculous lung lesions accumulate triglycerides. Consequently, the biogenesis of foam cells varies with the underlying disease. In vitro mechanistic studies showed that triglyceride accumulation in human macrophages infected with Mycobacterium tuberculosis is mediated by TNF receptor signaling through downstream activation of the caspase cascade and the mammalian target of rapamycin complex 1 (mTORC1). These features are distinct from the known biogenesis of atherogenic foam cells and establish a new paradigm for non-atherogenic foam cell formation. Moreover, they reveal novel targets for disease-specific pharmacological interventions against maladaptive macrophage responses. The formation of foam cells (lipid-laden macrophages) is a maladaptive host response associated with chronic inflammation. Foam cell biogenesis has been most thoroughly studied in atherosclerosis, where it is linked to disruption of cholesterol homeostasis and consequent intracellular accumulation of cholesteryl esters. In this study, we show that, during pulmonary tuberculosis, foam cells found in necrotizing granulomas (tubercles) accumulate predominantly triglycerides rather than cholesteryl esters. Triglyceride profiles are highly conserved across lung granulomas in rabbits, non-human primates, and humans. We also show that triglyceride accumulation in human primary macrophages infected with Mycobacterium tuberculosis involves TNF receptor signaling and downstream activation of mTORC1 and caspase pathways. Our finding that tuberculous foam cells differ from atherogenic foam cells with respect to storage lipid composition and lipid accumulation mechanism reveals that foam cell formation is a disease-specific process. The results of this study point to novel targets for pharmacological intervention against tuberculosis and help explain links between tuberculosis and insulin resistance.
