Leptin signaling impairs macrophage defenses against Salmonella Typhimurium

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 33; pp. 16551 - 16560
• Main Authors: Fischer, Julia, Gutièrrez, Saray, Ganesan, Raja, Calabrese, Chiara, Ranjan, Rajeev, Cildir, Gökhan, Hos, Nina Judith, Rybniker, Jan, Wolke, Martina, Fries, Jochen W. U., Tergaonkar, Vinay, Plum, Georg, Antebi, Adam, Robinson, Nirmal
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.08.2019
• Series: PNAS Plus
• Subjects: Ablation; activation; Adult; AKT; AKT protein; Animals; Bacterial infections; Biological Sciences; cells; Crosstalk; expression; Farmaceutisk vetenskap; Female; Gram-negative bacteria; host-defense; Humans; Immune clearance; Immune response; Immune system; Immunity; infection; Infections; Inflammation - pathology; Innate immunity; leptin; Leptin - antagonists & inhibitors; Leptin - metabolism; lysosome; lysosomes; Lysosomes - metabolism; Macrophages; Macrophages - immunology; Macrophages - microbiology; Mechanistic Target of Rapamycin Complex 2 - metabolism; Metabolism; Mice; Mice, Inbred C57BL; Models, Biological; pathogen; Pathogens; Phagosomes - metabolism; Pharmaceutical Sciences; Phosphoprotein Phosphatases - metabolism; Phosphorylation; PNAS Plus; Proto-Oncogene Proteins c-akt - metabolism; RAW 264.7 Cells; receptor; Receptors, Leptin - metabolism; Regulators; Rodents; Salmonella; Salmonella Infections, Animal; Salmonella typhimurium - immunology; Signal Transduction; Signaling; Young Adult; Salmonella; macrophages; AKT; lysosomes; leptin
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1904885116

The dynamic interplay between metabolism and immune responses in health and disease, by which different immune cells impact on metabolic processes, are being increasingly appreciated. However, the potential of master regulators of metabolism to control innate immunity are less understood. Here, we studied the cross-talk between leptin signaling and macrophage function in the context of bacterial infections. We found that upon infection with Gram-negative pathogens, such as Salmonella Typhimurium, leptin receptor (Lepr) expression increased in both mouse and human macrophages. Unexpectedly, both genetic Lepr ablation in macrophages and global pharmacologic leptin antagonization augmented lysosomal functions, reduced S. Typhimurium burden, and diminished inflammation in vitro and in vivo. Mechanistically, we show that leptin induction activates the mTORC2/Akt pathway and subsequently down-regulates Phlpp1 phosphatase, allowing for phosphorylated Akt to impair lysosomal-mediated pathogen clearance. These data highlight a link between leptin signaling, the mTORC2/Phlpp1/Akt axis, and lysosomal activity in macrophages and have important therapeutic implications for modulating innate immunity to combat Gram-negative bacterial infections.