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Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16551-16560. doi: 10.1073/pnas.1904885116. Epub 2019 Jul 26.

Leptin signaling impairs macrophage defenses against Salmonella Typhimurium.

Author information

1
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
2
Department I of Internal Medicine, University of Cologne, D-50937 Cologne, Germany.
3
Division of Infectious Diseases, University of Cologne, D-50937 Cologne, Germany.
4
Partner Site Bonn-Cologne, German Center for Infection Research (DZIF), D-50931 Cologne, Germany.
5
Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
6
Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50935 Cologne, Germany.
7
Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide SA 5001, Australia.
8
Institute of Pathology, University of Cologne, D-50931 Cologne, Germany.
9
Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology, Proteos, 138673 Singapore, Singapore.
10
Department of Biochemistry, National University of Singapore (NUS), 117597 Singapore.
11
Department of Pathology, Yong Loo Lin School of Medicine, NUS, 117597 Singapore.
12
Molecular Genetics of Ageing Laboratory, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
13
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; nirmal.robinson@unisa.edu.au.

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.

KEYWORDS:

AKT; Salmonella; leptin; lysosomes; macrophages

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