Impact of Semaphorin 7A on the Control of Inflammation-Resolution Programs

• Applicant: Professorin Dr. Valbona Mirakaj
• Subject Area: Anaesthesiology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320501009

• Final Report Year: 2023

Final Report Abstract

Treatment options for patients suffering from shock, sepsis, or ischemia-reperfusion injury have been sparse. A hallmark of these conditions is acute inflammatory responses that underlie basic pathophysiological mechanisms to protect the host. However, when these processes get out of control, acute inflammation can lead to collateral tissue destruction and loss of functional organ integrity. Control of excessive leukocyte recruitment is critical during the initial immune response, and in the context of resolution of inflammation, adequate clearance is essential for the ultimate restoration of tissue homeostasis. Recent studies have revealed biological parallels and interactions between the nervous and immune systems, demonstrating crucial effects in inflammatory events. The class of semaphorins is being increasingly recognized as playing important roles in immune function. Semaphorin 7A (Sema7A), one such guidance protein with chemoattractant and chemorepulsive properties, has been shown to have a critical role in axonal growth. Its importance in processes of inflammation-resolution was previously unknown. In this project we could identify 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 pro-resolving 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 proresolving lipid mediators. Signaling network analysis indicated that Sema7A induced the metabolic reprogramming of MΦ by activating the mTOR- and AKT2-signaling pathways. Administration of Sema7A SL4cd orchestrated the resolution response to tissue homeostasis by shortening the resolution interval, promoting tissue protection in murine peritonitis, and enhancing survival in polymicrobial sepsis. In summary, this project allowed us to uncover the critical role of Sema7A in linking metabolic reprogramming and the resolution of inflammation. This may deepen our understanding of the processes involved in the resolution of inflammation in innervated organs and may also provide therapeutic value for the treatment of excessive inflammation such as sepsis in the future.

Publications

• DIVI 2017 Leipzig "Die Rolle des Neuronalen Guidance Proteins Plexin C1 während der Entzündungsresolution"
  Andreas Körner, Alice Bernard & Valbona Mirakaj
  
• HAI 2017 Berlin "Das Neuronale Guidance Protein Semaphorin 7A beeinflusst die Entzündungsresolution und führt zu einem verlängerten Überleben in einem murinen Sepsismodell"
  Andreas Körner, Julia Theurer, Martin Giera & Valbona Mirakaj
  
• Immunomodulatory Functions of Neuronal Guidance Proteins. Trends in Immunology, 38(6), 444-456.
  Mirakaj, Valbona & Rosenberger, Peter
  
• Resolution of inflammation and sepsis survival are improved by dietary Ω-3 fatty acids. Cell Death & Differentiation, 25(2), 421-431.
  Körner, Andreas; Schlegel, Martin; Theurer, Julia; Frohnmeyer, Hannes; Adolph, Michael; Heijink, Marieke; Giera, Martin; Rosenberger, Peter & Mirakaj, Valbona
  
• Inhibition of neogenin fosters resolution of inflammation and tissue regeneration. Journal of Clinical Investigation, 128(10), 4711-4726.
  Schlegel, Martin; Körner, Andreas; Kaussen, Torsten; Knausberg, Urs; Gerber, Carmen; Hansmann, Georg; Jónasdóttir, Hulda Soffia; Giera, Martin & Mirakaj, Valbona
  
• WAT 2018 Würzburg "Plexin C1 induziert den pro-resolutionären Phänotyp von Monozyten/Makrophagen und dient als Survival-Marker"
  Andreas Körner, Alice Bernard & Valbona Mirakaj
  
• Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution. Proceedings of the National Academy of Sciences, 116(41), 20623-20634.
  Körner, Andreas; Zhou, Enchen; Müller, Christoph; Mohammed, Yassene; Herceg, Sandra; Bracher, Franz; Rensen, Patrick C. N.; Wang, Yanan; Mirakaj, Valbona & Giera, Martin
  
• Sympathetic nervous system controls resolution of inflammation via regulation of repulsive guidance molecule A. Nature Communications, 10(1).
  Körner, Andreas; Schlegel, Martin; Kaussen, Torsten; Gudernatsch, Verena; Hansmann, Georg; Schumacher, Timo; Giera, Martin & Mirakaj, Valbona
  
• WAT 2019 Würzburg "Semaphorin 7A induziert den pro-resolutionären Phänotyp von Monozyten/Makrophagen und beeinflusst deren Metabolismus"
  Andreas Körner & Valbona Mirakaj
  
• Novel Resolution Mediators of Severe Systemic Inflammation. ImmunoTargets and Therapy, Volume 9, 31-41.
  Gudernatsch, Verena; Stefańczyk, Sylwia Anna & Mirakaj, Valbona
  
• Mesenchymal Stem Cell Therapy for Severe COVID-19 ARDS. Journal of Intensive Care Medicine, 36(6), 681-688.
  Häberle, Helene; Magunia, Harry; Lang, Peter; Gloeckner, Henning; Körner, Andreas; Koeppen, Michael; Backchoul, Tamam; Malek, Nisar; Handgretinger, Rupert; Rosenberger, Peter & Mirakaj, Valbona
  
• Sema7A is crucial for resolution of severe inflammation. Proceedings of the National Academy of Sciences, 118(9).
  Körner, Andreas; Bernard, Alice; Fitzgerald, Julia C.; Alarcon-Barrera, Juan Carlos; Kostidis, Sarantos; Kaussen, Torsten; Giera, Martin & Mirakaj, Valbona