Sema7A is crucial for resolution of severe inflammation
Open Access
- 26 February 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (9)
- https://doi.org/10.1073/pnas.2017527118
Abstract
Endogenous mediators regulating acute inflammatory responses in both the induction and resolution phases of inflammatory processes are pivotal in host defense and tissue homeostasis. Recent studies have identified neuronal guidance proteins characterized in axonal development that display immunomodulatory functions. Here, we identify the neuroimmune guidance cue Semaphorin 7A (Sema7A), which appears to link macrophage (MΦ) metabolic remodeling to inflammation resolution. Sema7A orchestrated MΦ chemotaxis and chemokinesis, activated MΦ differentiation and polarization toward the proresolving M2 phenotype, and promoted leukocyte clearance. Peritoneal MΦSema7A−/− displayed metabolic reprogramming, characterized by reductions in fatty acid oxidation and oxidative phosphorylation, increases in glycolysis and the pentose phosphate pathway, and truncation of the tricarboxylic acid cycle, which resulted in increased levels of the intermediates succinate and fumarate. The low accumulation of citrate in MΦSema7A−/− correlated with the decreased synthesis of prostaglandins, leading to a reduced impact on lipid-mediator class switching and the generation of specialized pro resolving lipid mediators. Signaling network analysis indicated that Sema7A induced the metabolic reprogramming of MΦ by activating the mTOR- and AKT2-signaling pathways. Administration of Sema7ASL4cd orchestrated the resolution response to tissue homeostasis by shortening the resolution interval, promoting tissue protection in murine peritonitis, and enhancing survival in polymicrobial sepsis.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (DFG-MI 1506/5-1)
- Deutsche Forschungsgemeinschaft (374031971-TRR)
- EC | Horizon 2020 (MSCA-ITN-ETN, 812890)
- fortuene (2377-0-0)
This publication has 39 references indexed in Scilit:
- The Untapped Opportunity and Challenge of Immunometabolism: A New Paradigm for Drug DiscoveryCell Metabolism, 2019
- Immunometabolism at the interface between macrophages and pathogensNature Reviews Immunology, 2019
- Immunomodulatory Functions of Neuronal Guidance ProteinsTrends in Immunology, 2017
- Immunometabolism governs dendritic cell and macrophage functionThe Journal of Experimental Medicine, 2015
- Proresolving Lipid Mediators and Mechanisms in the Resolution of Acute InflammationImmunity, 2014
- Macrophage biology in development, homeostasis and diseaseNature, 2013
- Endothelial Semaphorin 7A promotes neutrophil migration during hypoxiaProceedings of the National Academy of Sciences of the United States of America, 2012
- Intestinal Epithelial Cell-Derived Semaphorin 7A Negatively Regulates Development of Colitis via αvβ1 IntegrinThe Journal of Immunology, 2012
- Semaphorins and their receptors in immune cell interactionsNature Immunology, 2007
- Resolution of inflammation: the beginning programs the endNature Immunology, 2005