Mycobacterium tuberculosis Keto-Mycolic Acid and Macrophage Nuclear Receptor TR4 Modulate Foamy Biogenesis in Granulomas: A Case of a Heterologous and Noncanonical Ligand-Receptor Pair
Mycobacterium tuberculosis Keto-Mycolic Acid and Macrophage Nuclear Receptor TR4 Modulate Foamy Biogenesis in Granulomas: A Case of a Heterologous and Noncanonical Ligand-Receptor Pair
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DOI：
10.4049/jimmunol.1400092
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发表时间：
2014-07-01
影响因子：
4.4
通讯作者：
Gupta, Pawan
中科院分区：
文献类型：
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作者：
Dkhar, Hedwin Kitdorlang;Nanduri, Ravikanth;Gupta, Pawan
结核分枝杆菌的细胞壁由生物活性脂类构成，这些脂类对毒力至关重要，并可能参与泡沫巨噬细胞（FMs）和肉芽肿的形成。我们最近的工作建立了结核分枝杆菌细胞壁脂质与宿主脂感核受体TR4之间的串扰。在这项研究中，我们从宿主孤儿NR TR4的结核分枝杆菌脂库中鉴定、鉴定并采用了一种异源配体酮霉菌酸。细胞壁脂质与TR4之间的串扰通过反激活和启动子报告子实验进行了分析。与其他细胞壁脂质相比，霉菌酸（MA）对TR4具有显著的反激活作用。在MA中，氧合形式keto-MA负责转激活，并通过TR4结合试验、TLC和核磁共振验证了其身份。等温滴定量热法显示酮- ma与TR4的结合在能量上是有利的。通过体外和体内肉芽肿形成模型评估，这个酮-MA- tr4轴似乎对氧合MA诱导FMs和肉芽肿形成至关重要。TR4与酮- ma结合具有宿主核受体与细菌脂质的独特关联，并增加了目前已知的膳食脂质的配体库。这种异源轴的药理学调节可能有望作为一线结核病药物的辅助治疗。
The cell wall of Mycobacterium tuberculosis is configured of bioactive lipid classes that are essential for virulence and potentially involved in the formation of foamy macrophages (FMs) and granulomas. Our recent work established crosstalk between M. tuberculosis cell wall lipids and the host lipid-sensing nuclear receptor TR4. In this study, we have characterized, identified, and adopted a heterologous ligand keto-mycolic acid from among M. tuberculosis lipid repertoire for the host orphan NR TR4. Crosstalk between cell wall lipids and TR4 was analyzed by transactivation and promoter reporter assays. Mycolic acid (MA) was found to transactivate TR4 significantly compared with other cell wall lipids. Among the MA, the oxygenated form, keto-MA, was responsible for transactivation, and the identity was validated by TR4 binding assays followed by TLC and nuclear magnetic resonance. Isothermal titration calorimetry revealed that keto-MA binding to TR4 is energetically favorable. This keto-MA-TR4 axis seems to be essential to this oxygenated MA induction of FMs and granuloma formation as evaluated by in vitro and in vivo model of granuloma formation. TR4 binding with keto-MA features a unique association of host nuclear receptor with a bacterial lipid and adds to the presently known ligand repertoire beyond dietary lipids. Pharmacologic modulation of this heterologous axis may hold promise as an adjunct therapy to frontline tuberculosis drugs.