PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

• Published in: The Journal of immunology (1950) 2017-04, Vol.198 (8), p.3283-3295
• Main Authors: Kim, Yi Sak, Lee, Hye-Mi, Kim, Jin Kyung, Yang, Chul-Su, Kim, Tae Sung, Jung, Mingyu, Jin, Hyo Sun, Kim, Sup, Jang, Jichan, Oh, Goo Taeg, Kim, Jin-Man, Jo, Eun-Kyeong
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Autophagy - physiology; Bacteria; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - immunology; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Biosynthesis; Bone marrow; Catabolism; Cell activation; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fluorescent Antibody Technique; Immunity, Innate - immunology; Immunoblotting; Immunohistochemistry; Infections; Inflammation; Lipid Droplets - immunology; Lipid metabolism; Lipid Metabolism - immunology; Lipids; Macrophages; Macrophages - immunology; Macrophages - microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mycobacterium; Mycobacterium Infections - immunology; Mycobacterium tuberculosis; Oxidation; Peroxisome proliferator-activated receptors; Phagocytosis; Polymerase Chain Reaction; PPAR alpha - immunology; PPAR alpha - metabolism; Transcription activation; Tuberculosis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601920

The role of peroxisome proliferator-activated receptor α (PPAR-α) in innate host defense is largely unknown. In this study, we show that PPAR-α is essential for antimycobacterial responses via activation of transcription factor EB (TFEB) transcription and inhibition of lipid body formation. PPAR-α deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. PPAR-α agonists promoted autophagy, lysosomal biogenesis, phagosomal maturation, and antimicrobial defense against or bacillus Calmette-Guérin. PPAR-α agonists regulated multiple genes involved in autophagy and lysosomal biogenesis, including , , and in bone marrow-derived macrophages. Silencing of TFEB reduced phagosomal maturation and antimicrobial responses, but increased macrophage inflammatory responses during mycobacterial infection. Moreover, PPAR-α activation promoted lipid catabolism and fatty acid β-oxidation in macrophages during mycobacterial infection. Taken together, our data indicate that PPAR-α mediates antimicrobial responses to mycobacterial infection by inducing TFEB and lipid catabolism.