DAMP-induzierte proinflammatorische Feedback-Mechanismen zwischen Phagozyten und endothelialen/epithelialen Barrieren in infektiösen Erkrankungen

    Das Immunsystem reagiert schnell und effektiv gegen eindringende Pathogene. Die Immunantwort wird durch die Freisetzung des Alarmins S100A8/A9 verstärkt, das über einen TLR4 abhängigen Signalweg weitere Immunzellen aktiviert. S100A8/A9 inaktiviert sich selbst durch eine calcium-abhängige Tetramerbildung, was die Immunantwort lokal begrenzt. In der letzten Förderperiode wollen wir die Auswirkungen untersuchen, wenn dieser Regulationsmechanismus in infektiösen Mausmodellen außer Kraft gesetzt ist und daraus Strategien entwickeln, diesen Signalweg zu blockieren bzw. zu neutralisieren.

    Forschungsgebiet: Phagozytenbiologie, Gefahrensignalisierung

    Prof. Dr. rer. nat. Thomas Vogl

    Projektlaufzeit: Juli 2012 - Juni 2024

    • Publikationen

      Originalartikel

      • Hoffmann E, Gerwing M, Niland S, Niehoff R, Masthoff M, Geyer C, Wachsmuth L, Wilken E, Höltke C, Heindel WL, Hoerr V, Schinner R, Berger P, Vogl T, Eble JA, Maus B, Helfen A, Wildgruber M, Faber C (2023) Profiling specific cell populations within the inflammatory tumor microenvironment by oscillating-gradient diffusion-weighted MRI. J Immunother Cancer 11: e006092.  doi:  10.1136/jitc-2022-006092. 
      • Hoffmann E, Schache D, Holtke C, Soltwisch J, Niland S, Krahling T, Bergander K, Grewer M, Geyer C, Groeneweg L, Eble JA, Vogl T, Roth J, Heindel W, Maus B, Helfen A, Faber C, Wildgruber M, Gerwing M, Hoerr V (2023) Multiparametric chemical exchange saturation transfer MRI detects metabolic changes in breast cancer following immunotherapy. J Transl Med 21: 577.  doi: 10.1186/s12967-023-04451-6. 
      • McNally A, Berger P, Wolf J, Kaiser K, Chetrusca Covash A, Robeck S, Pastau I, Fehler O, Jauch-Speer SL, Hermann S, Schäfers M, Van Gorp H, Kanneganti A, Dehoorne J, Haerynck F, Penco F, Gattorno M, Chae JJ, Kubes P, Lamkanfi M, Wullaert A, Sperandio M, Vogl T, Roth J, Austermann J (2023) Complex regulation of alarmins S100A8/A9 and secretion via gasdermin D pores exacerbates autoinflammation in familial Mediterranean fever.  J Allergy Clin Immunol 152(1): 230–243. doi.org/10.1016/j.jaci.2023.01.037. 
      • Möller A, Jauch-Speer S L, Gandhi S, Vogl T, Roth J, Fehler O (2023) The roles of toll-like receptor 4, CD33, CD68, CD69, or CD147/EMMPRIN for monocyte activation by the DAMP S100A8/S100A9. Front Immunol 14: 1110185. doi.org/10.3389/fimmu.2023.1110185
      • Rorch SK, McNally A, Berger P, Wolf J, Kaiser K, Chetrusca Covash A, Robeck S, Pastau I, Fehler O, Jauch-Speer SL, Hermann S, Schäfers M, Van Gorp H, Kanneganti A, Dehoorne J, Haerynck F, Penco F, Gattorno M, Chae JJ, Kubes P, Lamkanfi M, Wullaert A, Sperandio M, Vogl T, Roth J, Austermann J (2023) Complex regulation of alarmins S100A8/A9 and secretion via gasdermin D pores exacerbates autoinflammation in familial Mediterranean fever. J Allergy Clin Immunol 152(1): 230-243.  doi: 10.1016/j.jaci.2023.01.037.
      • von Wulffen M, Luehrmann V, Robeck S, Russo A, Fischer-Riepe L, van den Bosch M, van Lent P, Loser K, Gabrilovich DI, Hermann S, Roth J, Vogl T (2023) S100A8/A9-alarmin promotes local myeloid-derived suppressor cell activation restricting severe autoimmune arthritis. Cell Rep 42: 113006. doi: 10.1016/j.celrep.2023.113006.
      • Wolf M, Joseph R, Austermann J, Scharrnbeck-Davis C, Hermann S, Roth J, Vogl T (2023) S100A8/S100A9 Integrates F-Actin and Microtubule Dynamics to Prevent Uncontrolled Extravasation of Leukocytes. Biomedicines, 11(3), 835. doi.org/10.3390/biomedicines11030835
      • Aulin C, Larsson S, Vogl T, Roth J, Åkesson A, Swärd P, Heinbäck R, Erlandsson Harris H, Struglics A (2022) The alarmins high mobility group box protein 1 and S100A8/A9 display different inflammatory profiles after acute knee injury. Osteoarthritis Cartilage 30(9): 1198-1209.  doi: 10.1016/j.joca.2022.06.009. 
      • Jauch-Speer SL, Herrera-Rivero M, Ludwig N, Véras De Carvalho BC, Martens L, Wolf J, Imam Chasan A, Witten A, Markus B, Schieffer B, Vogl T, Rossaint J, Stoll M, Roth J, Fehler O (2022) C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9. eLife 11: e75594. doi: 10.7554/eLife.75594.
      • Russo A, Schürmann H, Brandt M, Scholz K, Matos ALL, Grill D, Revenstorff J, Rembrink M, von Wulffen M, Fischer-Riepe L, Hanley PJ, Häcker H, Prünster M, Sánchez-Madrid F, Hermann S, Klotz L, Gerke V, Betz T, Vogl T, Roth J (2022) Alarming and Calming: Opposing Roles of S100A8/S100A9 Dimers and Tetramers on Monocytes. Adv Sci (Weinh) 9(36): e2201505.  doi: 10.1002/advs.202201505. 
      • Schürmann H, Abbasi F, Russo A, Hofemeier AD, Brandt M, Roth J, Vogl T, Betz T (2022) Analysis of monocyte cell tractions in 2.5D reveals mesoscale mechanics of podosomes during substrate-indenting cell protrusion. J Cell Sci 135(10): jcs259042. doi:10.1242/jcs.259042.
      • Schwarz C, Buchholz R, Jawad M, Hoesker V, Terwesten-Solé C, Karst U, Linsen L, Vogl T, Hoerr V, Wildgruber M, Faber C (2022) Fingerprints of Element Concentrations in Infective Endocarditis Obtained by Mass Spectrometric Imaging and t-Distributed Stochastic Neighbor Embedding. ACS Infect Dis 8(2): 360-372.  doi: 10.1021/acsinfecdis.1c00485.
      • Christmann C, Zenker S, Martens L, Hübner J, Loser K, Vogl T, Roth J (2021) Interleukin 17 promotes expression of alarmins S100A8 and S100A9 during the inflammatory response of keratinocytes. Front Immun 11: 599947.  doi: 10.3389/fimmu.2020.599947.
      • Stahl LS, Roth J, Rudack C, McNally A, Weber J, Vogl T, Spiekermann C (2021) Evaluation of the QUANTUM BLUE sCAL rapid test as a point of care tool to identify patients with peritonsillar abscess. Sci Rep 11(1): 4497. doi: 10.1038/s41598-021-84027-w
      • Pirr S, Dauter L, Vogl T, Ulas T, Bohnhorst B, Roth J, Viemann D (2021) S100A8/A9 is the first predictive marker for neonatal sepsis. Clin Transl Med 11(4): e338.  doi: 10.1002/ctm2.338.
      • Frohberger SJ, Fercoq F, Neumann AL, Surendar J, Stamminger W, Ehrens A, Karunakaran I, Remion E, Vogl T, Hoerauf A, Martin C, Hübner MP (2020) S100A8/S100A9 deficiency increases neutrophil activation and protective immune responses against invading infective L3 larvae of the filarial nematode Litomosoides sigmodontis. PLoS Negl Trop Dis  14(2): e0008119. doi:10.1371/journal.pntd.0008119.
      • Helfen A, Grosse Hokamp N, Geyer C, Heindel W, Bremer C, Vogl T, Höltke C, Masthoff M, Barczyk-Kahlert K, Roth J, Wildgruber M, Eisenblaetter M (2020) Target-Specific Imaging of Cathepsin and S100A8/A9 Reflects Specific Features of Malignancy and Enables Estimation of Tumor Malignancy. Mol Imaging Biol 22(1): 66-72. doi:10.1007/s11307-019-01370-1.
      • Leite Dantas R, Bettenworth D, Varga G, Weinhage T, Wami HT, Dobrindt U, Roth J, Vogl T, Ludwig S, Wixler V. (2020) Spontaneous onset of TNFα-triggered colonic inflammation depends on functional T lymphocytes, S100A8/A9 alarmins, and MHC H-2 haplotype. J Pathol 251(4):388-399. doi: 10.1002/path.5473
      • Li L, Song J, Chuquisana O, Hannocks MJ, Loismann S, Vogl T, Roth J, Hallmann R, Sorokin L (2020) Endothelial Basement Membrane Laminins as an Environmental Cue in Monocyte Differentiation to Macrophages. Front Immunol 11:584229. doi:10.3389/fimmu.2020.584229
      • Torrico M, Bobadilla-Lozoya K, Vogl T, Walzl G, du Plessis N, Kaushal D, Scriba T, Zuñiga J,  Khader S (2020) S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis. Clin Invest 130(6): 3098-3112. doi:10.1172/JCI130546
      • Seethaler A, Stenner M, McNally A, Rudack C, Roth J, Vogl T, Spiekermann C (2020)  IL-8 and IFN-γ as Preoperative Predictors of the Outcome of Tonsillectomy. Ear Nose Throat J. 100(5_suppl):822S-827S. doi:10.1177/0145561320910682
      • Willers M, Ulas T, Völlger L, Vogl T, Heinemann AS, Pirr S, Pagel J, Fehlhaber B, Halle O, Schöning J, Schreek S, Löber U, Essex M, Hombach P, Graspeuntner S, Basic M, Bleich A, Cloppenborg-Schmidt K, Künzel S, Jonigk D, Rupp J, Hansen G, Förster R, Baines JF, Härtel C, Schultze JL, Forslund SK, Roth J, Viemann D (2020) S100A8 and S100A9 are Important for Postnatal Development of Gut Microbiota and Immune System in Mice and Infants. Gastroenterology. 159(6):2130-2145.e5. doi:10.1053/j.gastro.2020.08.019
      • Dreschers S, Ohl K, Lehrke M, Möllmann J, Denecke B, Costa I, Vogl T, Viemann D, Roth J, Orlikowsky T, Tenbrock K. (2019) Impaired cellular energy metabolism in cord blood macrophages contributes to abortive response toward inflammatory threats. Nat Commun 10:1685.
      • Helfen A, Große Hokamp N, Geyer C, Heindel W, Bremer C, Vogl T, Höltke C, Masthoff M, Barczyk-Kahlert K, Roth J, Wildgruber M, Eisenblaetter M. (2019) Target-Specific Imaging of Cathepsin and S100A8/A9 Reflects Specific Features of Malignancy and Enables Estimation of Tumor Malignancy. Mol Imaging Biol 2019 May 16. doi: 10.1007/s11307-019-01370-1.
      • Völler T, Faust A, Roth J, Schäfers M, Vogl T, Hermann S (2018) A non-peptidic S100A9 specific ligand for optical imaging of phagocyte activity in vivo, Mol Imaging Biol 20(3):407-416.
      • Vogl T, Stratis A, Wixler V, VöllerT, Thurainayagam S, Jorch SK, Zenker S, Dreiling A, Chakraborty D, Fröhling M, Paruzel P, Wehmeyer C, Hermann S, Papantonopoulou O, Geyer C, Loser K, Schäfers M, Ludwig S, Stoll M, Leanderson T, Schultze JL, Koenig S, Pap T & Roth J (2018) Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation, J. Clin. Invest. pii: 89867. (doi: 10.1172/JCI89867)   .
      • Vogl T, Stratis A, Wixler V, Völler T, Thurainayagam S, Jorch SK, Zenker S, Dreiling A, Chakraborty D, Fröhling M, Paruzel P, Wehmeyer C, Hermann S, Papantonopoulou O, Geyer C, Loser K, Schäfers M, Ludwig S, Stoll M, Leandersson T, Schultze JL, König S, Pap T, Roth J. (2018) Auto-inhibitory regulation of S100A8/A9-alarmin activity locally restricts sterile inflammation. J Clin Invest 128:1852-1866.
      • Chakraborty D, Zenker S, Rossaint J, Hölscher A, Pohlen M, Zarbock A, Roth J and Vogl T (2017) Alarmin S100A8 Activates Alveolar Epithelial Cells in the Context of Acute Lung Injury in a TLR4-Dependent Manner. Front. Immunol. 8:1493. (doi: 10.3389/fimmu.2017.01493)
      • Dantas RL, Brachvogel B, Schied T, Bergmeier V, Skryabin B, Vogl T, Ludwig S & Wixler V (2017) The LIM-Only Protein Fhl2 Attenuates Development of Psoriatic Arthritis by Blocking Adam17-Mediated TNF Release. Am. J. Pathol. 187, 2388-2398. (doi: 10.1016/j.ajpath.2017.07. 015)
      • Eisenblätter M, Flores-Borja F, Lee JJ, Wefers C, Smith H, Hueting R, Cooper MS, Blower PJ, Patel D, Rodriguez-Justo M, Milewicz H, Vogl T, Roth J, Tutt A, Schaeffter T & Ng T (2017) Visualization of tumor-immune interaction - target-specific imaging of S100A8/A9 reveals pre-metastatic niche establishment. Theranostics 7, 2392-2401. (doi: 10.7150/thno.17138)
      • Pirr S, Richter M, Fehlhaber B, Pagel J, Härtel C, Roth J, Vogl T and Viemann D (2017) High Amounts of S100-Alarmins Confer Antimicrobial Activity on Human Breast Milk Targeting Pathogens Relevant in Neonatal Sepsis. Front. Immunol. 8:1822. (doi: 10.3389/fimmu.2017.01822)
      • Spiekermann C, Russo A, Stenner M, Rudack C, Roth J & Vogl T (2017) Increased levels of S100A8/A9 in patients with peritonsillar abscess – a new promising diagnostic marker to differentiate between peritonsillar abscess and peritonsillitis. Dis. Markers 2017:9126560. (doi: 10.1155/2017/9126560)
      • Thölking G, Schuette-Nuetgen K, Vogl T, Dobrindt U, Kahl BC, Brand M, et al. (2017) Male kidney allograft recipients at risk for urinary tract infection? PLoS ONE 12(11): e0188262. (doi.org/10.1371/journal.pone.0188262)
      • Ulas T, Pirr S, Fehlhaber B, Bickes M, Loof TG, Vogl T, Mellinger L, Heinemann AS, Burgmann J, Schöning J, Schreek S, Pfeifer S, Reuner F, Völlger L, Stanulla M, von Köckritz-Blickwede M, Glander S, Barczyk-Kahlert K, von Kaisenberg CS, Friesenhagen J, Fischer-Riepe L, Zenker S, Schultze JL, Roth J & Viemann D (2017) S100-induced innate immune programming protects newborn infants from sepsis. Nat Immunol. 18, 622-632. (doi: 10.1038/ni.3745)
      • Dantas R, Masemann D, Schied T, Bergmeier V, Vogl T, Loser K, Brachvogel B, Varga G, Ludwig S & Wixler V (2016) Macrophage-mediated psoriasis can be suppressed by regulatory T lymphocytes. J Pathol. 240, 366-377. (doi: 10.1002/path.4786)
      • Heinemann AS, Pirr S, Fehlhaber B, Mellinger L, Burgmann J, Busse M, Ginzel M, Friesenhagen J, von Köckritz-Blickwede M, Ulas T, von Kaisenberg CS, Roth J, Vogl T & Viemann D (2016) In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. FASEB J. 31, 1153-1164. (doi: 10.1096/fj.201601083R)
      • Wales P, Schuberth CE, Aufschnaiter R, Fels J, García-Aguilar I, Janning A, Dlugos CP, Schäfer-Herte M, Klingner C, Wälte M, Kuhlmann J, Menis E, Hockaday KL, Maier KC, Hou W, Russo A, Higgs HN, Pavenstädt H, Vogl T, Roth J, Qualmann B, Kessels MM, Martin DE, Mulder B & Wedlich-Söldner R (2016) Calcium-mediated actin reset (CaAR) mediates acute cell adaptations. Elife Dec 6;5. pii: e19850. (doi: 10.7554/eLife.19850)
      • Becker A, Große Hokamp N, Zenker S, Flores-Borja F, Barzcyk K, Varga G, Roth J, Geyer C, Heindel W, Bremer C, Vogl T*, Eisenblaetter M* (2015) In vivo visualisation of the alarmin S100A9 in tumor lesions allows for estimation of the individual malignant potential by evaluation of tumor host-cell interaction. J. Nuc. Med. 56:450-456. *Shared first or senior authorship
      • Fassl SK, Austermann J, Papantonopoulou O, Riemenschneider M, Xue J, Bertheloot D, Freise N, Spiekermann C, Witten A, Viemann D, Kirschnek S, Stoll M, Latz E, Schultze JL, Roth J, Vogl T (2015) Transcriptome assessment reveals a dominant role for TLR4 in the activation of human phagocytes by the alarmin MRP8. J. Immunol. 194:575-583.
      • Pruenster M, Kurz ARM, Chung KJ, Cao-Ehlker X, Bieber S, Nussbaum CF, Bierschenk S, Eggersmann TK, Rohwedder I, Heinig K, Immler R, Moser M, Koedel U, Gran S, McEver RP, Vestweber D, Verschoor A, Leandersson T, Chavakis T, Roth J, Vogl T,* Sperandio M* (2015) Extracellular MRP8/14 is a regulator of β2 integrin-dependent neutrophil slow rolling and adhesion. Nat Commun. 6:6915.
      • Van Crombruggen K, Vogl T, Pérez-Novo C, Holtappels G, Bachert C (2015) Differential release and deposition of S100A8/A9 proteins in inflamed upper airway tissue. Eur Respir J, in press [Oct 22. pii: ERJ-00159-2015. doi:10.1183/13993003.00159-2015].
      • Wache C, Klein M, Ostergaard C, Angele B, Häcker H, Pfister HW, Pruenster M, Sperandio M, Leanderson T, Roth J, Vogl T, Koedel U (2015) Myeloid-related protein 14 promote inflammation and injury in meningitis. J Infect Dis (in press).  (pii: jiv028. Epub ahead of print)
      • Austermann J, Friesenhagen J, Fassl SK, Ortkras T, Burgmann J, Barczyk-Kahlert K, Faist E, Zedler S, Pirr S, Rohde C, Müller-Tidow C, von Köckritz-Blickwede M, von Kaisenberg CS, Flohé SB, Ulas T, Schultze JL, Roth J, Vogl T, Viemann D (2014) Alarmins MRP8 and MRP14 Induce Stress Tolerance in Phagocytes under Sterile Inflammatory Conditions.Cell Rep 9(6): 2112-2123. (doi: 10.1016/j.celrep.2014.11.020. Epub 2014 Dec 11)
      • Vogl T, Eisenblätter M, Völler T, Zenker S, Hermann S, van Lent P, Faust A, Geyer C, Petersen B, Roebrock K, Schäfers M, Bremer C, Roth J (2014) Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity. Nat Commun 5: 4593.
      • Petersen B, Wolf M, Austermann J, van Lent PLEM, Foell D, Ahlmann M, Kupas V, Loser K, Sorg C, Roth J, Vogl T (2013) The alarmin Mrp8/14 as regulator of the adaptive immune response during allergic contact dermatitis. EMBO J 32: 100-111. [IF: 9.82]
      • Foell D, Wittkowski H, Kessel C, Lüken A, Weinhage T, Varga G, Vogl T, Wirth T, Viemann D, Björk P, van Zoelen MAD, Gohar F, Srikrishna G, Kraft M, Roth J (2013) Pro-inflammatory S100A12 can activate human monocytes via Toll-like Receptor 4. Am J Respir Crit Care Med 187: 1324-1334. [IF: 11.04]
      • Kuipers MT*, Vogl T*, Aslami H, Jongsma G, van den Berg E, Vlaar APJ, Roelofs JJTH, Juffermans NP, Schultz MJ, van der Poll T, Roth J, Wieland CW (2013) High levels of S100A8/A9 proteins aggravate ventilator-induced lung injury via TLR4 signaling. PLoS One 8: e68694. [IF: 3.73] * Both authors made equal contributions.
      • Gopal R, Monin L, Torres D, Slight S, Mehra S, McKenna K, Fallert-Junecko BA, Reinhart TA, Kolls J, Báez-Saldaña R, Cruz-Lagunas A, Rodríguez-Reyna TS, Kumar NP, Tessier P, Roth J, Selman M, Becerril-Villanueva E, Baquera-Heredia J, Cumming B, Kasprowicz VO, Steyn AJ, Babu S, Kaushal D, Zúñiga J, Vogl T, Rangel-Moreno J, Khader SA (2013) S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. Am J Respir Crit Care Med 188: 1137-1146. [IF: 11.04]