Universität zu Köln

Fischer, Julia, Gutierrez, Saray, Ganesan, Raja, Calabrese, Chiara, Ranjan, Rajeev, Cildir, Gokhan, Hos, Nina Judith, Rybniker, Jan, Wolke, Martina, Fries, Jochen W. U., Tergaonkar, Vinay, Plum, Georg, Antebi, Adam and Robinson, Nirmal ORCID: 0000-0002-7361-9491 (2019). Leptin signaling impairs macrophage defenses against Salmonella Typhimurium. Proc. Natl. Acad. Sci. U. S. A., 116 (33). S. 16551 - 16561. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fischer, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Gutierrez, Saray UNSPECIFIED UNSPECIFIED UNSPECIFIED Ganesan, Raja UNSPECIFIED UNSPECIFIED UNSPECIFIED Calabrese, Chiara UNSPECIFIED UNSPECIFIED UNSPECIFIED Ranjan, Rajeev UNSPECIFIED UNSPECIFIED UNSPECIFIED Cildir, Gokhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Hos, Nina Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Rybniker, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolke, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Fries, Jochen W. U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tergaonkar, Vinay UNSPECIFIED UNSPECIFIED UNSPECIFIED Plum, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Antebi, Adam UNSPECIFIED UNSPECIFIED UNSPECIFIED Robinson, Nirmal UNSPECIFIED orcid.org/0000-0002-7361-9491 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-144420
DOI:	10.1073/pnas.1904885116
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	116
Number:	33
Page Range:	S. 16551 - 16561
Date:	2019
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HOST-DEFENSE; INFECTION; RECEPTOR; CELLS; ACTIVATION; EXPRESSION; LYSOSOME; PATHOGEN Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14442