Chemotaktische Formylpeptidrezeptoren in der Aktivierung und trans-endothelialen Migration von Leukozyten

    Formyl-Peptid-Rezeptoren (FPRs) erkennen ein breites Spektrum von verschiedenen Pathogen-assoziierten Molekülen und andere endogene Liganden, einschließlich pro-entzündlichen Mitochondrien-Peptiden und des entzündungshemmenden Annexin A1 (AnxA1). Um zu verstehen, wie FPRs verschiedene Signalwege mit gegensätzlichen Antworten ansteuern können ("biased agonism"), werden wir agonistenspezifische Fingerabdrücke der FPR-Aktivierung analysieren sowie die Dynamik FPR-haltiger supramolekularer Komplexe untersuchen. AnxA1 wird durch unkonventionelle Mechanismen sezerniert. Wir wollen die durch dynamische Wechselwirkungen zwischen Leukozyten und Endothelzellen verursachten endothelialen Plasmamembranwunden charakterisieren, und die Reparaturmaschinerie als möglichen Mechanismus der AnxA1-Freisetzung analysieren.

     

    Forschungsgebiet: Leukozytenbiologie, Endothelzellbiologie

    Prof. Dr. rer. nat. Ursula Rescher
    Prof. Dr. rer. nat. Volker Gerke

    Projektlaufzeit: Juli 2012 - Juni 2024

    • Publikationen

      Originalartikel

      • Goretzko J, Pauels I, Heitzig N, Thomas K, Kardell M, Naß J, Krogsaeter EK, Schloer S, Spix B, Linard Matos AL, Leser C, Wegner T, Glorius F, Bracher F, Gerke V, Rossaint J, Grimm C, Rescher U (2023) P-selectin-dependent leukocyte adhesion is governed by endolysosomal two-pore channel 2. Cell Rep. 42(12):113501. doi:10.1016/j.celrep.2023.113501
      • Kroll MK, Schloer S, Candan P, Korthals N, Wenzel C, Ihle H, Gilhaus K, Liedtke KR, Schöfbänker M, Surmann B, Schröter R, Neugebauer U, Mall G, Oswald S, Ludwig S, Rescher U, Vollenbröker B, Ciarimboli G (2023) Importance of ACE2 for SARS-CoV-2 Infection of Kidney Cells. Biomolecules, 13(3), 472. doi:10.3390/biom13030472
      • Raj N, Greune L, Kahms M, Mildner K, Franzkoch R, Psathaki OE, Zobel T, Zeuschner D, Klingauf J, Gerke V (2023) Early Endosomes Act as Local Exocytosis Hubs to Repair Endothelial Membrane Damage. Adv Sci (Weinh) 10(13): e2300244. doi:10.1002/advs.202300244.
      • Faist A, Schloer S, Mecate-Zambrano A, Janowski J, Schreiber A, Boergeling Y, Conrad BCG, Kumar S, Toebben L, Schughart K, Baumgardt M, Kessler M, Hoenzke K, Hocke A, Trautmann M, Hartmann W, Kato H, Rescher U, Christersson A, Kuehn J, Mellmann A, Wolff T, Kuempers P, Rovas A, Wiewrodt R, Wiebe K, Barth P, Ludwig S, Brunotte L (2023) Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier. Antiviral Res. 209: 105475. doi:10.1016/j.antiviral.2022.105475 Epub 2022 Nov 21.
      • Ashraf AP, Gerke V (2022) The resealing factor S100A11 interacts with annexins and extended synaptotagmin-1 in the course of plasma membrane wound repair. Front Cell Dev Biol 10. doi: 10.3389/fcell.2022.968164
      • Kummer S, Lander A, Goretzko J, Kirchoff N, Rescher U, Schloer S (2022) Pharmacologically induced endolysosomal cholesterol imbalance through clinically licensed drugs itraconazole and fluoxetine impairs Ebola virus infection in vitro. Emerg Microbes Infect. 11(1):195-207. doi:10.1080/22221751.2021.2020598
      • Schloer S, Goretzko J, Rescher U (2022) Repurposing Antifungals for Host-Directed Antiviral Therapy? Pharmaceuticals (Basel) 15(2): 212. doi:10.3390/ph15020212
      • Schloer S, Treuherz D, Faist A, de Witt M, Wunderlich K, Wiewrodt R, Wiebe K, Barth P, Wälzlein JH, Kummer S, Balkema-Buschmann A, Ludwig S, Brunotte L, Rescher U (2022) 3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases. Emerg Microbes Infect. 11(1):2160-2175. doi:10.1080/22221751.2022.2117101
      • Schreiber A, Ambrosy B, Planz O, Schloer S, Rescher U, Ludwig S (2022) The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs. Pharmaceutics. 14(9):1776. doi:10.3390/pharmaceutics14091776
      • Ashraf A, Gerke V (2021) Plasma membrane wound repair is characterized by extensive membrane lipid and protein rearrangements in vascular endothelial cells. BBA Mol Cell Res 1868: 118991
      • Brunotte L, Zheng S, Mecate-Zambrano A, Tang J, Ludwig S, Rescher U, Schloer S. (2021) Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro. Pharmaceutics. 13(9):1400. doi:10.3390/pharmaceutics13091400
      • Schloer S, Brunotte L, Mecate-Zambrano A, Zheng S, Tang J, Ludwig S, Rescher U (2021) Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro. Br J Pharmacol. 178(11):2339-2350. doi:10.1111/bph.15418
      • Schloer S, Brunotte L, Goretzko J, Mecate-Zambrano A, Korthals N, Gerke V, Ludwig S, Rescher U (2020) Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine. Emerg Microbes Infect. 2020;9(1):2245-2255. doi:10.1080/22221751.2020.1829082
      • Schloer S, Goretzko J, Pleschka S, Ludwig S, Rescher U (2020) Combinatory Treatment with Oseltamivir and Itraconazole Targeting Both Virus and Host Factors in Influenza A Virus Infection. Viruses 12(7): 703.  doi: 10.3390/v12070703.
      • Holthenrich A, Drexler HCA, Chehab T, Naß J, Gerke V (2019) Proximity proteomics of endothelial Weibel-Palade bodies identifies novel regulator of von-Willebrand factor secretion. Blood 134: 979-982.
      • Schloer S, Hübel N, Masemann D, Pajonczyk D, Brunotte L, Ehrhardt C, Brandenburg LO, Ludwig S, Gerke V, Rescher U (2019a) The annexin A1/FPR2 signaling axis expands alveolar macrophages, limits viral replication, and attenuates pathogenesis in the murina influenza A virus infection model. FASEB J 33(11):12188-12199. doi: 10.1096/fj.201901265R.
      • Schloer S, Goretzko J, Kuehnl A, Brunotte L, Ludwig S, Rescher U (2019b) The clinically licensed antifungal drug itraconazole inhibits influenza virus in vitro and in vivo. Emerg Microbes Infect 8: 80-93.
      • Krischuns T, Günl F, Henschel L, Binder M, Willemsen J, Schloer S, Rescher U, Gerlt V, Zimmer G, Nordhoff C, Ludwig S, Brunotte L (2018) Phosphorylation of TRIM28 Enhances the Expression of IFN-beta and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells. Front Immunol 9: 2229.
      • Kühnl A, Musiol A, Heitzig N, Johnson DE, Ehrhardt C, Grewal T, Gerke V, Ludwig S, Rescher U (2018) Late endosomal/lysosomal cholesterol accumulation is a host cell-protective mechanism inhibiting endosomal escape of influenza A virus. mBio 9: pii:e01345-18.
      • Boye LT, Maeda K, Pezeshkian W, Sønder LS, Hager CS, Gerke V, Simonsen AC, Nylandsted J (2017). Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair. Nat Commun 8: 1623.
      • Heitzig N, Brinkmann BF, Koerdt SN, Rosso G, Shahin V, Rescher U (2017). Annexin A8 promotes VEGF-A driven endothelial cell sprouting. Cell Adh Migr. 11: 275-287.
      • Heitzig N, Kühnl A, Grill D, Ludewig K, Schloer S, Galla HJ, Grewal T, Gerke V, Rescher U (2018). Cooperative binding promotes demand-driven recruitment of AnxA8 to cholesterol containing membranes. BBA Mol Cell Biol Lipids 1863: 349-358.
      • Koerdt S, Gerke V (2017). Annexin A2 is involved in Ca2+-dependent plasma membrane repair in primary human endothelial cells. BBA Mol Cell Res 1864: 1046-1053.
      • Lueck K, Carr A-J F, Stampoulis D, Gerke V, Rescher U, Greenwood J & Moss S E (2017). Regulation of retinal pigment epithelial cell phenotype by Annexin A8. Scientific Reports, 7, 4638. (doi.org/10.1038/s41598-017-03493-3)
      • Poeter M, Brandherm I, Rossaint J, Rosso G, Shahin V, Skryabin BV, Zabock A, Gerke V, Rescher U (2014) Annexin A8 controls leucocyte recruitment to activated endothelial cells via cells surface delivery of CD63. Nature Commun 5: 3738. (doi: 10.1038/ncomms4738, 28 April 2014-06-05)
      • Ghavampour S, Lange C, Bottino C, Gerke V (2013) Transcriptional profiling of human monocytes identifies the inhibitory receptor CD300a as regulator of transendothelial migration. PLOS One 8 (9): e73981.
      • Musiol A, Gran S, Ehrhardt C, Ludwig S, Grewal T, Gerke V, Rescher U (2013) Annexin A6-balanced late endosomal cholesterol controls Influenza A replication and propagation.MBio 4(6): e00608-13. (doi: 10.1128/mBio.00608-13

      Reviews

      • Raabe C, Gröper J, Rescher U (2019). Biased perspectives on formyl peptide receptors. BBA Mol Cell Res 1866: 305-316.