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PPAR-Α Activation Mediates Innate Host Defense Through Induction of TFEB and Lipid Catabolism

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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 This information is current as Yi Sak Kim, Hye-Mi Lee, Jin Kyung Kim, Chul-Su Yang, of September 28, 2021. Tae Sung Kim, Mingyu Jung, Hyo Sun Jin, Sup Kim, Jichan Jang, Goo Taeg Oh, Jin-Man Kim and Eun-Kyeong Jo J Immunol published online 8 March 2017 http://www.jimmunol.org/content/early/2017/03/08/jimmun ol.1601920 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/03/08/jimmunol.160192 Material 0.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 8, 2017, doi:10.4049/jimmunol.1601920 The Journal of Immunology PPAR-a Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism Yi Sak Kim,*,†,1 Hye-Mi Lee,*,1 Jin Kyung Kim,*,† Chul-Su Yang,‡ Tae Sung Kim,*,† Mingyu Jung,†,x Hyo Sun Jin,* Sup Kim,*,† Jichan Jang,{ Goo Taeg Oh,‖ Jin-Man Kim,†,x and Eun-Kyeong Jo*,† The role of peroxisome proliferator–activated receptor a (PPAR-a) in innate host defense is largely unknown. In this study, we show that PPAR-a is essential for antimycobacterial responses via activation of transcription factor EB (TFEB) transcription and inhibition of lipid body formation. PPAR-a deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. PPAR-a agonists promoted autophagy, lysosomal biogenesis, phagosomal maturation, and antimicrobial defense against Mycobacterium tuberculosis or M. bovis bacillus Calmette–Gue´rin. PPAR-a agonists regulated multiple genes involved in autophagy and lysosomal biogenesis, including Lamp2, Rab7, and Tfeb in bone marrow–derived Downloaded from macrophages. Silencing of TFEB reduced phagosomal maturation and antimicrobial responses, but increased macrophage in- flammatory responses during mycobacterial infection. Moreover, PPAR-a activation promoted lipid catabolism and fatty acid b-oxidation in macrophages during mycobacterial infection. Taken together, our data indicate that PPAR-a mediates anti- microbial responses to mycobacterial infection by inducing TFEB and lipid catabolism. The Journal of Immunology, 2017, 198: 000–000. http://www.jimmunol.org/ uclear receptor peroxisome proliferator–activated re- retinoids, and cholesterol metabolites, saturated and unsaturated ceptor a (PPAR-a) is a PPAR isoform that regulates the fatty acids, as well as pharmacologic agents (4, 5). PPAR-a is a N expression of genes involved in glucose and lipid transcription factor that binds to cis-acting DNA elements, metabolism as well as inflammatory processes (1–3). All PPAR i.e., PPAR response elements in the promoter region of numerous members belong to the adopted orphan nuclear receptor family target genes (6). Through the regulation of these target genes, and are activated by various endogenous ligands, such as steroids, PPAR-a acts as a key regulator of energy metabolism, and mi- tochondrial and peroxisomal function (2, 4, 7). In addition, PPAR- a is responsible for activation of fatty acid b-oxidation (FAO) and by guest on September 28, 2021 *Department of Microbiology, Chungnam National University School of Medicine, ketogenesis and simultaneous inhibition of glycolysis and fatty Daejeon 35015, South Korea; †Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, South Korea; ‡Department of Mo- acid synthesis (2, 8). However, the function of PPAR-a in innate lecular and Life Science, College of Science and Technology, Hanyang University, host defense during mycobacterial infection is largely unknown. Ansan 15578, South Korea; xDepartment of Pathology, Chungnam National Univer- sity School of Medicine, Daejeon 35015, South Korea; {Molecular Mechanism of Mycobacterium tuberculosis is the major causative pathogen of Antibiotics, Division of Life Science, Research Institute of Life Science, Gyeongsang human tuberculosis (TB), an important infectious disease that ‖ National University, Jinju 52828, South Korea; and Department of Life Science, causes two million deaths per year worldwide (9). M. tuberculosis Ewha Womans University, Seoul 03760, South Korea is a highly successful pathogen that is capable of surviving and 1 Y.S.K. and H.-M.L. are cofirst authors. persisting within host phagocytes by inhibiting phagosomal mat- ORCIDs: 0000-0003-4918-961X (C.-S.Y.); 0000-0003-2812-0285 (M.J.). uration and escape from innate immune effectors (10, 11). In Received for publication November 11, 2016. Accepted for publication February 3, addition, pathogenic mycobacteria use host lipids to enter and 2017. multiply within non-maturing parasitophorous vacuoles in host This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, Ministry of Health and Welfare, Re- cells (12). Host macrophages use several strategies to clear viru- public of Korea (HI15C0395), by the National Research Foundation grant funded by lent mycobacteria. Autophagy, an intracellular lysosomal degra- the Korean government (MSIP) (NRF-2015M3C9A2054326) at Chungnam National dation process, is an important cell-autonomous defense system University. involved in innate and adaptive immune responses and thus con- Address correspondence and reprint requests to Prof. Eun-Kyeong Jo, Departments of Microbiology and Medical Science, Chungnam National University School of Med- tributes to host defense against various intracellular microbes in- icine, 6 Munhwa-dong, Jungku, Daejeon 301-747, South Korea. E-mail address: cluding M. tuberculosis and M. bovis bacillus Calmette–Gue´rin [email protected] (BCG) (13). Among the transcription factors implicated in auto- The online version of this article contains supplemental material. phagy, transcription factor EB (TFEB) is a critical regulator of Abbreviations used in this article: AHR, aryl hydrocarbon receptor; Atg, autophagy- autophagic activation (14, 15). TFEB transcriptionally regulates related gene; BCG, bacillus Calmette–Gue´rin; BMDM, bone marrow–derived mac- numerous genes involved in multiple steps of autophagy, includ- rophage; COX-2, cyclooxygenase 2; ERFP, enhanced red fluorescent protein; FAO, fatty acid b-oxidation; IHC, immunohistochemistry; Lamp, lysosomal-associated ing autophagosomal and lysosomal biogenesis and substrate tar- membrane protein; mCherry-EGFP-LC3B, tandem fluorescent-tagged LC3; MOI, geting and degradation (15). Furthermore, TFEB is required for multiplicity of infection; OCR, oxygen consumption rate; PBST, PBS plus 0.05% Tween-80; PPAR-a, Ppara, peroxisome proliferator–activated receptor a; qPCR, the expression of genes involved in lipid degradation and FAO in quantitative real-time PCR; Rab, Ras-related protein in brain; RT, room temperature; mitochondria (16). shRNA, short hairpin RNA; shTFEB, lentiviral shRNA specific to Tfeb; TB, tuber- In this study we identified a critical role for PPAR-a in host culosis; TFEB, transcription factor EB. defense against M. tuberculosis and BCG mycobacterial infec- Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 tions, mediated by the ability of PPAR-a to directly activate the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601920 2 PPAR-a AGONISTS ACTIVATE ANTIBACTERIAL AUTOPHAGY expression of genes involved in autophagosomal and lysosomal histopathological score was assigned to each tissue in each animal based biogenesis and function. In addition, PPAR-a activation led to on the extent of granulomatous inflammation as follows: 0 = no lesion, 1 = upregulation and nuclear translocation of TFEB, which is required minimal lesion (1–10% of tissue in section involved), 2 = mild lesion (11– 30% involved), 3 = moderate lesion (30–50% involved), 4 = marked lesion for lysosomal biogenesis and antimicrobial responses against M. (50–80% involved), and 5 = severe lesion (.80% involved), as described tuberculosis infection. Furthermore, PPAR-a activation inhibited previously (20). lipid body formation and promoted the expression of genes in- For IHC staining, lung paraffin sections (4 mm) were cut and immu- volved in FAO in macrophages, suggesting a role for PPAR-a in nostained with Abs specific for cyclooxygenase 2 (COX-2) (ab15191; Abcam), anti-Ly-6G6C Ab (ab2557, NIMP-R14; Abcam), and TNF-a (sc- lipid catabolism during mycobacterial infection. 52746; Santa Cruz). IHC staining tissue slides for COX-2 and neutrophils were imaged using an Aperio ScanScope CS System and confocal images Materials and Methods were taken with a Leica TCS SP8 confocal system and processed with the Mice Leica LAS AF Lite program. The histopathological score data used for this study were provided
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