Einfluss der PlexinB1 / Semaphorin4D Achse auf die Entzündungsreaktion während eines Lungenschadens
Zusammenfassung der Projektergebnisse
The Acute Respiratory Distress Syndrome (ARDS) is a high mortality syndrome with significant public health impact. The pathophysiology of ARDS is characterized by self-propagating inflammation within the lung, in which neutrophil recruitment the alveolar space plays a fundamental role. Neuronal Guidance Proteins (NGPs) influence the neutrophil migration and hold immunomodulatory potential. Here, we aimed to investigate the function of the NGP semaphorin4D (Sema4D) in regulating neutrophil adhesion, polarization, transmigration and consequently its involvement in the pathogenesis of ARDS. For this, leukocyte adhesion was evaluated in flow chamber experiments. The fibrinogen binding assay and the expression of integrins on neutrophils were performed by flow cytometry (FACS). The neutrophil polarization was induced by fMLP concentration gradient in chemotaxis chambers and investigated by immunofluorescence (IF). Proteomics assay and IF was employed for the pathway molecular mechanism investigation. The expression of Sema4D and its receptors PlxnB1 and PlxnB2 were evaluated with IF and flow cytometry in vitro and in vivo model. Sema4D knock-out mice were used to determine the severity of inflammation in the lung with BCA assay for protein concentration, ELISA for inflammatory cytokines, and MPO assay. We found that Sema4D inhibited leukocyte adhesion at the inflammatory site by influencing their affinity for binding fibrinogen. Sema4D suppressed neutrophils polarization, the redistribution of PSGL-1 to the uropod, and subsequently neutrophil firm adhesion in inflammation. These processes were dependent on Sema4D binding to its receptors PlxnB1 and PlxnB2. Proteomics analysis showed that Sema4D regulated the activation of RhoA and Rac, and subsequently influenced the F-actin and myosin activation. In inflammation, the expression of Sema4D and its receptors declined on neutrophils, but the expression of Sema4D on pulmonary endothelial and epithelial cells increased significantly. Sema4D deficiency led to increased inflammatory action in the lung. In summary we found that Sema4D inhibits neutrophils polarization and adhesion, subsequently influence the recruitment of neutrophils into lung interstitial and alveolar space, and control the severity of inflammatory action in the lung. This function depends on its binding to PlxnB1 and PlxnB2 through which Sema4D regulates the activation of RhoA and Rac, subsequently influences the intracellular cytoskeleton activation. This enables Sema4D to become a promising therapeutic target for the treatment of ARDS in the future.
Projektbezogene Publikationen (Auswahl)
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Die Semaphorin4D – PlexinB1 Achse beeinflusst die hypoxische Inflammation. Leipzig, Deutschland, 18. Kongress der Deutschen Interdisziplinären Vereinigung für Intensivmedizin und Notfallmedizin (DIVI), Dezember 05-07, 2018, Programmheft S. 149, EP/06/01, E-Poster, poster presentation
Günther S., D. Köhler, T. Granja, C. Eggstein & P. Rosenberger
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Semaphorin 4D dampens inflammatory lung injury. Leipzig, Deutschland, 18. Kongress der Deutschen Interdisziplinären Vereinigung für Intensivmedizin und Notfallmedizin (DIVI), Dezember 05-07, 2018, Programmheft S. 67, FPV/01/03, oral presentation
Granja T., M. Blaha, C. Eggstein, D. Köhler & P. Rosenberger
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Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort. Critical Care, 25(1).
Magunia, Harry; Lederer, Simone; Verbuecheln, Raphael; Gilot, Bryant Joseph; Koeppen, Michael; Haeberle, Helene A.; Mirakaj, Valbona; Hofmann, Pascal; Marx, Gernot; Bickenbach, Johannes; Nohe, Boris; Lay, Michael; Spies, Claudia; Edel, Andreas; Schiefenhövel, Fridtjof; Rahmel, Tim; Putensen, Christian; Sellmann, Timur; Koch, Thea ... & Rosenberger, Peter
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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
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Neuronal Guidance Protein Semaphorin4D influences inflammatory lung injury. Germany, the 21st Congress of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI 21 VIRTUELL) 01 - 03.12.2021, Online poster presentation
Tang L., T. Granja, D. Köhler, M. Blaha, S. Günther & P. Rosenberger
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Neuronal guidance proteins in cardiovascular inflammation. Basic Research in Cardiology, 116(1).
Keller, Marius; Mirakaj, Valbona; Koeppen, Michael & Rosenberger, Peter
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Neuronal Guidance Protein Semaphorin4D influences inflammatory lung injury. Bad Urach, Germany, Ph.D. Retreat of the Medicine Faculty - University Tübingen, 23.06.2022, Poster presentation
Tang L., T. Granja, D. Köhler, M. Blaha, S. Günther & P. Rosenberger
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COVID-19 does not influence functional status after ARDS therapy. Critical Care, 27(1).
Bernard, Alice; Serna-Higuita, Lina Maria; Martus, Peter; Mirakaj, Valbona; Koeppen, Michael; Zarbock, Alexander; Marx, Gernot; Putensen, Christian; Rosenberger, Peter & Haeberle, Helene Anna
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Inhaled prostacyclin therapy in the acute respiratory distress syndrome: a randomized controlled multicenter trial. Respiratory Research, 24(1).
Haeberle, Helene A.; Calov, Stefanie; Martus, Peter; Serna-Higuita, Lina Maria; Koeppen, Michael; Goll, Almuth; Bernard, Alice; Zarbock, Alexander; Meersch, Melanie; Weiss, Raphael; Mehrländer, Martin; Marx, Gernot; Putensen, Christian; Bakchoul, Tamam; Magunia, Harry; Nieswandt, Bernhard; Mirakaj, Valbona & Rosenberger, Peter
