Leptin signaling impairs macrophage defenses against Salmonella Typhimurium Julia Fischer, Saray Gutièrrez, Raja Ganesan, Chiara Calabrese, Rajeev Ranjan, Gökhan Cildir, Nina Judith Hos, Jan Rybniker, Martina Wolke, Jochen W. U. Fries, Vinay Tergaonkar, Georg Plum, Adam Antebi, Nirmal Robinson Proceedings of the National Academy of Sciences Aug 2019, 116 (33) 16551-16560; DOI: 10.1073/pnas.1904885116
Abstract:
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.
License type:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Funding Info:
This work was supported by funding from DZIF and Cologne Fortune Starter Grant (to J.F.) and from CECAD (funded by the Deutsche Forschungsgemeinschaft [DFG] within the Excellence Initiative by the German federal and state governments), Köln Fortune, and Maria-Pesch, University clinic, Cologne, grants from DFG (SFB 670) (to N.R.). The LepRfl/fl mice were kindly provided by Jens C. Brüning and Streamson Chua, who was funded by NIH New York Nutrition Obesity Research Center Grant 1PO1DK26687.