PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism
PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism
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DOI：
10.4049/jimmunol.1601920
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发表时间：
2017-04-15
影响因子：
4.4
通讯作者：
Jo, Eun-Kyeong
中科院分区：
文献类型：
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作者：
Kim, Yi Sak;Lee, Hye-Mi;Jo, Eun-Kyeong
过氧化物酶体增殖物激活受体α（PPAR-alpha）在宿主先天防御中的作用在很大程度上是未知的。在这项研究中，我们表明，PPAR-alpha是通过激活转录因子EB（TFEB）转录和抑制脂质体形成的抗分枝杆菌反应所必需的。PPAR-alpha缺乏导致分枝杆菌感染期间细菌负荷增加和炎症反应加剧。PPAR-alpha激动剂促进自噬、溶酶体生物发生、吞噬体成熟和抗结核分枝杆菌或M.牛卡介苗PPAR-alpha激动剂调节参与自噬和溶酶体生物发生的多个基因，包括骨髓源性巨噬细胞中的Lamp 2、Rab 7和Tfeb。沉默TFEB减少吞噬体成熟和抗菌反应，但增加巨噬细胞炎症反应在分枝杆菌感染。此外，在分枝杆菌感染期间，PPAR-alpha激活促进巨噬细胞中的脂质催化剂和脂肪酸β-氧化。总之，我们的数据表明，PPAR-alpha介导的抗微生物反应，分枝杆菌感染诱导TFEB和脂质catalysts。
The role of peroxisome proliferator-activated receptor a (PPAR-alpha) in innate host defense is largely unknown. In this study, we show that PPAR-alpha is essential for antimycobacterial responses via activation of transcription factor EB (TFEB) transcription and inhibition of lipid body formation. PPAR-alpha deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. PPAR-alpha agonists promoted autophagy, lysosomal biogenesis, phagosomal maturation, and antimicrobial defense against Mycobacterium tuberculosis or M. bovis bacillus Calmette-Guerin. PPAR-alpha agonists regulated multiple genes involved in autophagy and lysosomal biogenesis, including Lamp2, Rab7, and Tfeb in bone marrow-derived macrophages. Silencing of TFEB reduced phagosomal maturation and antimicrobial responses, but increased macrophage inflammatory responses during mycobacterial infection. Moreover, PPAR-alpha activation promoted lipid catabolism and fatty acid beta-oxidation in macrophages during mycobacterial infection. Taken together, our data indicate that PPAR-alpha mediates antimicrobial responses to mycobacterial infection by inducing TFEB and lipid catabolism.