Molecular mechanisms of E-selectin induced rapid NLRP3 inflammasome activation in neutrophils

Recruitment of circulating neutrophils into inflamed tissue follows a cascade of adhesion and activation events involving an intimate interplay between the inflamed endothelium and neutrophils. During the first funding period we have discovered a rapid E-selectin-mediated process leading to NLRP3 inflammasome activation and subsequent Gasdermin D pore formation, which allows release of the alarmin S100A8/A9 from neutrophils. Intriguingly, this process was self-limiting with removal of the formed Gasdermin D pores within minutes after E-selectin stimulation through the ESCRT-III membrane repair machinery. In the second funding period, we intend to follow up on this rapid NLRP3 inflammasome activation process in neutrophils and investigate the exact molecular mechanisms of E-selectin- dependent signalling pathways leading to NLRP3 inflammasome activation and Gasdermin D pore formation as well as activation of the voltage-gated K+ channel KV1.3 which provides K+- efflux critical for NLRP3 activation. In addition, we clarify how ESCRT-III is triggered and how Ninj-1/2 are regulated in E-selectin stimulated neutrophils. Finally, we explore how the NLRP3 inflammasome and KV1.3 influence disease severity in a clinically relevant ischemic kidney model.

Sperandio
Markus, MD

MGK

LMU

Institute of Cardiovascular Physiology and Pathophysiology

Team

Immler
Roland, PostDoc

LMU

Publications

C2 C7 E Preimplantation Factor (PIF) Is an Endogenous Inhibitor of Potassium Channel KV 1.3 Regulating Neutrophil Function during Pregnancy Immler, R.; Nadolni, W.; Franz, J. M.; Bertsch, A.; Baasch, S.; Morikis, V. A.; Kurova, A.; Borso, M.; Forné, I.; Itang, E. C. M.; Müller-Reif, J. B.; Pruenster, M.; Wackerbarth, L. M.; Napoli, M.; Rohwedder, I.; Yevtushenko, A.; Rauer, M.; Kolben, M.; Moser, M.; Barnea, E.; Boerries, M.; Vogl, T.; Simon, S. I.; Klein, C.; Henneke, P.; Imhof, A.; Zierler, S.; Sperandio, M. 2026 bioRxiv https://doi.org/10.64898/2026.03.20.713251
C2 The Dual Non-Competitive CXCR1/2 Inhibitor Ladarixin Impairs Neutrophil Extravasation without Altering Intravascular Adhesion Napoli, M.; Sitaru, S.; Budke, A.; Kammerl, A.; Querner, G.; Immler, R.; Rohwedder, I.; Seifert, S.; Ferraro, B.; Weckbach, L.; Catz, S.; Aramini, A.; Amendola, P. G.; Allegretti, M.; Bertini, R.; Pruenster, M.; Sperandio, M. 2026 Haematologica https://doi.org/10.3324/haematol.2025.287877
A2 C2 Tryptophan Depletion Generates Hyper-Reactive Portal Neutrophils in Alcoholic Liver Disease Reinartz Groba, S.; Richter, M.; Schwarz, D.; Seyfried, P.; Serafimov, K.; Fu, X.; Farinola, L.; Heming, J.-N.; Masthoff, M.; Köhler, M.; Zarbock, A.; Sohrabi, Y.; Praktiknjo, M.; Rambold, A. S.; Chevre, R.; Lämmerhofer, M.; Trebicka, J.; Soehnlein, O. 2026 Gut https://doi.org/10.1136/gutjnl-2025-337646
A7 C2 Beyond Ion Flux: The Potassium Channel KV1.3 and Its Regulatory Function in Neutrophils Ku, J.; Anders, H.-J.; Sperandio, M.; Immler, R. 2026 Curr Opin Immunol https://doi.org/10.1016/j.coi.2026.102750
A3 A5 C2 Z1 G-CSF/NAMPT Signaling Drives Neutrophil Dysfunction and Enhances Bacterial Infection Susceptibility in Cancer Patients Pylaeva, E.; Tollrian, L.; Riedesel, J.; Shevchuk, O.; Thiel, I.; Ozel, I.; Kabankova, N.; Voß, H.; Siebels, B.; Schlüter, H.; Haist, C.; Hanenberg, H.; Mattheis, S.; Kürten, C.; Sperandio, M.; Kehrmann, J.; Engel, D. R.; Lang, S.; Jablonska, J. 2025 Nat Commun https://doi.org/10.1038/s41467-025-67471-4
C2 The Dual Non-Competitive CXCR1/2 Inhibitor Ladarixin Impairs Neutrophil Extravasation without Altering Intravascular Adhesion Napoli, M.; Sitaru, S.; Budke, A.; Kammerl, A.; Querner, G.; Immler, R.; Rohwedder, I.; Seifert, S.; Ferraro, B.; Weckbach, L.; Catz, S.; Aramini, A.; Amendola, P. G.; Allegretti, M.; Bertini, R.; Pruenster, M.; Sperandio, M. 2025 Haematologica https://doi.org/10.3324/haematol.2025.287877
C2 Posttranslational Sialylation and Its Impact on Neutrophil Recruitment Nussbaumer, K.; Marth, J. D.; Sperandio, M. 2025 J Leukoc Biol https://doi.org/10.1093/jleuko/qiaf113
C2 Development of a Circadian Immune System Li, X.; Rothämel, P.; Nussbaum, C.; Sperandio, M.; Scheiermann, C. 2025 Trends Immunol https://doi.org/10.1016/j.it.2025.06.004
C2 Bosutinib Mitigates Inflammation in Experimental Sepsis Cunha, C. M. C.; Abreu, V. H. P.; Estato, V.; Soares, G. M. V.; Moraes, B. P. T.; Oliveira, G. P.; Silva, J. D.; Silva, P. L.; Immler, R.; Rocco, P. R.; Sperandio, M.; Silva, A. R.; Bozza, P. T.; Castro-Faria-Neto, H. C.; Gonçalves-de-Albuquerque, C. F. 2025 Eur J Clin Invest https://doi.org/10.1111/eci.70055
C2 C3 B5 E C7 E Cytosolic S100A8/A9 Promotes Ca2+ Supply at LFA-1 Adhesion Clusters during Neutrophil Recruitment Napoli, M.; Immler, R.; Rohwedder, I.; Lupperger, V.; Pfabe, J.; Gonzalez Pisfil, M.; Yevtushenko, A.; Vogl, T.; Roth, J.; Salvermoser, M.; Dietzel, S.; Slak Rupnik, M.; Marr, C.; Walzog, B.; Sperandio, M.; Pruenster, M. 2024 Elife https://doi.org/10.7554/eLife.96810
C2 C7 E Neonatal neutrophils exhibit reduced NLRP3 inflammasome activation Wackerbarth, L. M.; Seifert, S. B.; Napoli, M.; Rohwedder, I.; Vogl, T.; Scheiermann, C.; Kolben, T.; Nussbaum, C.; Pruenster, M.; Immler, R.; Sperandio, M. 2024 J Leukoc Biol https://doi.org/10.1093/jleuko/qiae206
C2 CCR3-Dependent Eosinophil Recruitment Is Regulated by Sialyltransferase ST3Gal-IV Immler, R.; Nussbaumer, K.; Doerner, A.; El Bounkari, O.; Huber, S.; Abisch, J.; Napoli, M.; Schmidt, S.; Margraf, A.; Pruenster, M.; Rohwedder, I.; Lange-Sperandio, B.; Mall, M. A.; de Jong, R.; Ohnmacht, C.; Bernhagen, J.; Voehringer, D.; Marth, J. D.; Frommhold, D.; Sperandio, M. 2024 Proc Natl Acad Sci https://doi.org/10.1073/pnas.2319057121
C2 Cyclophilin A Is a Ligand for RAGE in Thrombo-Inflammation Seizer, P.; von Ungern-Sternberg, S. N. I.; Haug, V.; Dicenta, V.; Rosa, A.; Butt, E.; Nöthel, M.; Rohlfing, A.-K.; Sigle, M.; Nawroth, P. P.; Nussbaum, C.; Sperandio, M.; Kusch, C.; Meub, M.; Sauer, M.; Münzer, P.; Bieber, K.; Stanger, A.; Mack, A. F.; Huber, R.; Brand, K.; Lehners, M.; Feil, R.; Poso, A.; Krutzke, K.; Schäffer, T. E.; Nieswandt, B.; Borst, O.; May, A. E.; Zernecke, A.; Gawaz, M.; Heinzmann, D. 2024 Cardiovasc Res https://doi.org/10.1093/cvr/cvad189
C2 Circadian Clock and Hypoxia Sartor, F.; Ferrero-Bordera, B.; Haspel, J.; Sperandio, M.; Holloway, P. M.; Merrow, M. 2024 Circ Res https://doi.org/10.1161/CIRCRESAHA.124.323518
C2 Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation Arribas, V.; Onetti, Y.; Ramiro-Pareta, M.; Villacampa, P.; Beck, H.; Alberola, M.; Esteve-Codina, A.; Merkel, A.; Sperandio, M.; Martínez-Estrada, O. M.; Schmid, B.; Montanez, E. 2024 JCI Insight https://doi.org/10.1172/jci.insight.177819
A2 A3 A4 A5 A6 E A7 B1 B2 B3 B5 E C1 C2 C3 C5 AP1 Neutrophils - Biology and Diversity Maier-Begandt, D.; Alonso-Gonzalez, N.; Klotz, L.; Erpenbeck, L.; Jablonska, J.; Immler, R.; Hasenberg, A.; Mueller, T. T.; Herrero-Cervera, A.; Aranda-Pardos, I.; Flora, K.; Zarbock, A.; Brandau, S.; Schulz, C.; Soehnlein, O.; Steiger, S.; the TRR332 consortium. 2023 Nephrol Dial Transplant https://doi.org/10.1093/ndt/gfad266
B5 E C2 C7 E E-Selectin-Mediated Rapid NLRP3 Inflammasome Activation Regulates S100A8/S100A9 Release from Neutrophils via Transient Gasdermin D Pore Formation. Pruenster, M.; Immler, R.; Roth, J.; Kuchler, T.; Bromberger, T.; Napoli, M.; Nussbaumer, K.; Rohwedder, I.; Wackerbarth, L. M.; Piantoni, C.; Hennis, K.; Fink, D.; Kallabis, S.; Schroll, T.; Masgrau-Alsina, S.; Budke, A.; Liu, W.; Vestweber, D.; Wahl-Schott, C.; Roth, J.; Meissner, F.; Moser, M.; Vogl, T.; Hornung, V.; Broz, P.; Sperandio, M. 2023 Nat Immunol https://doi.org/10.1038/s41590-023-01656-1
A1 A2 C2 Z1 The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation Gatsiou, A.; Tual-Chalot, S.; Napoli, M.; Ortega-Gomez, A.; Regen, T.; Badolia, R.; Cesarini, V.; Garcia-Gonzalez, C.; Chevre, R.; Ciliberti, G.; Silvestre-Roig, C.; Martini, M.; Hoffmann, J.; Hamouche, R.; Visker, J. R.; Diakos, N.; Wietelmann, A.; Silvestris, D. A.; Georgiopoulos, G.; Moshfegh, A.; Schneider, A.; Chen, W.; Guenther, S.; Backs, J.; Kwak, S.; Selzman, C. H.; Stamatelopoulos, K.; Rose-John, S.; Trautwein, C.; Spyridopoulos, I.; Braun, T.; Waisman, A.; Gallo, A.; Drakos, S. G.; Dimmeler, S.; Sperandio, M.; Soehnlein, O.; Stellos, K. 2023 Immunity https://doi.org/10.1016/j.immuni.2023.03.021
A6 E C2 C3 C6 A20 and the Noncanonical NF-κB Pathway Are Key Regulators of Neutrophil Recruitment during Fetal Ontogeny Rohwedder, I.; Wackerbarth, L. M.; Heinig, K.; Ballweg, A.; Altstätter, J.; Ripphahn, M.; Nussbaum, C.; Salvermoser, M.; Bierschenk, S.; Straub, T.; Gunzer, M.; Schmidt-Supprian, M.; Kolben, T.; Schulz, C.; Ma, A.; Walzog, B.; Heinig, M.; Sperandio, M. 2023 JCI Insight https://doi.org/10.1172/jci.insight.155968
B5 E C2 C7 E Complex Regulation of Alarmins S100A8/A9 and Secretion via Gasdermin-D Pores Exacerbates Autoinflammation in Familial Mediterranean Fever Jorch, S. K.; McNally, A.; Berger, P.; Wolf, J.; Kaiser, K.; Chetrusca Covash, A.; Robeck, S.; Pastau, I.; Fehler, O.; Jauch-Speer, S.-L.; Hermann, S.; Schäfers, M.; Van Gorp, H.; Kanneganti, A.; Dehoorne, J.; Haerynck, F.; Penco, F.; Gattorno, M.; Chae, J. J.; Kubes, P.; Lamkanfi, M.; Wullaert, A.; Sperandio, M.; Vogl, T.; Roth, J.; Austermann, J. 2023 J Allergy Clin Immunol https://doi.org/10.1016/j.jaci.2023.01.037