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E-selectin-mediated rapid NLRP3 inflammasome activation regulates S100A8/S100A9 release from neutrophils via transient gasdermin D pore formation.

Nature immunology

Authors: Monika Pruenster, Roland Immler, Jonas Roth, Tim Kuchler, Thomas Bromberger, Matteo Napoli, Katrin Nussbaumer, Ina Rohwedder, Lou Martha Wackerbarth, Chiara Piantoni, Konstantin Hennis, Diana Fink, Sebastian Kallabis, Tobias Schroll, Sergi Masgrau-Alsina, Agnes Budke, Wang Liu, Dietmar Vestweber, Christian Wahl-Schott, Johannes Roth, Felix Meissner, Markus Moser, Thomas Vogl, Veit Hornung, Petr Broz, Markus Sperandio

S100A8/S100A9 is a proinflammatory mediator released by myeloid cells during many acute and chronic inflammatory disorders. However, the precise mechanism of its release from the cytosolic compartment of neutrophils is unclear. Here, we show that E-selectin-induced rapid S100A8/S100A9 release during inflammation occurs in an NLRP3 inflammasome-dependent fashion. Mechanistically, E-selectin engagement triggers Bruton's tyrosine kinase-dependent tyrosine phosphorylation of NLRP3. Concomitant potassium efflux via the voltage-gated potassium channel K1.3 mediates ASC oligomerization. This is followed by caspase 1 cleavage and downstream activation of pore-forming gasdermin D, enabling cytosolic release of S100A8/S100A9. Strikingly, E-selectin-mediated gasdermin D pore formation does not result in cell death but is a transient process involving activation of the ESCRT III membrane repair machinery. These data clarify molecular mechanisms of controlled S100A8/S100A9 release from neutrophils and identify the NLRP3/gasdermin D axis as a rapid and reversible activation system in neutrophils during inflammation.

© 2023. The Author(s).

PMID: 37903858

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