Plexin C1 modulates metabolic programming for resolution of severe inflammation

Cell Communication and Signaling, vol. 23, pp. 523

Abstract

Persistent, unresolved inflammatory processes disrupt the complex homeostatic state and lead to severe disease, ultimately resulting in organ failure, shock, and death. The mediators that monitor and control the programmed mechanisms in tissue homeostasis and repair remain elusive. A recently discovered group of endogenous proteins, termed neuronal guidance proteins (NGPs), has gained attention as important mediators of immunoregulation and tissue homeostasis through their role in the complex interplay between metabolic reprogramming and immunity. In murine peritonitis, the deficiency of the NGP Plexin C1 (PLXC1−/−) led to an increase in neutrophil and Ly6Chi monocyte recruitment to the injury site and a decrease in the phagocytosis rate. This was accompanied by a decrease in the endogenous biosynthesis of specialized proresolving lipid mediators (SPMs) such as Maresin-1 and Protectin DX and finally by a lengthening of the resolution interval. Peritoneal macrophages (MΦs)PLXC1−/− followed specific strategies to adapt their metabolism to catabolic conditions, by reducing fatty acid oxidation and oxidative phosphorylation, increasing aerobic glycolysis and activation of the pentose phosphate pathway, and disrupting the tricarboxylic acid cycle. The decreased MΦsPLXC1−/− citrate levels corresponded with a lipid mediator profile in which PGD2 and PGE2 were greatly decreased in murine PLXC1−/− peritoneal exudates, indicating a lesser effect on lipid mediator class switching and ultimately the formation of SPMs. Analysis of the related signaling networks indicated mTOR and AKT2 phosphorylation pathways are critical determinants of metabolic reprogramming in activated MΦsPLXC1−/−. These findings highlight a novel role for PLXC1 in regulating the crosstalk between immunometabolism and inflammation resolution programs in severe inflammation.

Authors 11

1. Andreas Körner

   University of Tübingen

   Affiliation as printed

   Department of Anesthesiology and Intensive Care Medicine, Molecular Intensive Care Medicine, University Hospital Eberhard Karls University, Tübingen, Germany

   Department of Anesthesiology and Intensive Care Medicine, University Hospital Eberhard Karls University, Tübingen, Germany

2. Michael Koeppen

   University of Tübingen

   Affiliation as printed

   Department of Anesthesiology and Intensive Care Medicine, University Hospital Eberhard Karls University, Tübingen, Germany

3. Jasvir Kaur

   University of Tübingen

   Affiliation as printed

   Department of Anesthesiology and Intensive Care Medicine, University Hospital Eberhard Karls University, Tübingen, Germany

4. Julia Catherine Fitzgerald

   Hertie Institute for Clinical Brain Research · University of Tübingen

   Affiliation as printed

   Hertie Institute for Clinical Brain Research, University Clinic Tübingen, Tübingen, Germany

5. Sarantos Kostidis Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics and Metabolomics, Leiden University Medical Center (LUMC), Leiden, The Netherlands

6. Torsten Kaussen

   Medizinische Hochschule Hannover

   Affiliation as printed

   Department of Pediatric Cardiology and Pediatric Intensive Care Medicine, Hannover Medical School, Hannover, Germany

7. Christoph Trautwein

   University of Tübingen

   Affiliation as printed

   Core Facility Metabolomics, Medical Faculty of Tübingen, University of Tübingen, Tübingen, Germany

   Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany

8. Martin A. Giera Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics and Metabolomics, Leiden University Medical Center (LUMC), Leiden, The Netherlands

9. Tamam Bakchoul

   Universitätsklinikum Tübingen · University of Tübingen

   Affiliation as printed

   Transfusion Medicine, Medical Faculty of Tübingen, University Hospital of Tübingen, Tübingen, Germany

10. Alice Marie Bernard

    University of Tübingen

    Affiliation as printed

    Department of Anesthesiology and Intensive Care Medicine, University Hospital Eberhard Karls University, Tübingen, Germany

11. Valbona Mirakaj corresponding

    Goethe University Frankfurt · University Hospital Frankfurt · University of Tübingen

    Affiliation as printed

    Department of Anesthesiology and Intensive Care Medicine, Molecular Intensive Care Medicine, University Hospital Eberhard Karls University, Tübingen, Germany. valbona.mirakaj@uni-tuebingen.de

    Department of Anesthesiology and Intensive Care Medicine, University Hospital Eberhard Karls University, Tübingen, Germany. valbona.mirakaj@uni-tuebingen.de

    Department of Anesthesiology, Intensive Care Medicine, and Pain, Translational Intensive Care Medicine, University Hospital Goethe University, Frankfurt, Germany. valbona.mirakaj@uni-tuebingen.de

    Department of Anesthesiology, Intensive Care Medicine, and Pain, Translational Intensive Care Medicine, University Hospital Goethe University, Frankfurt, Germany