2023-10-31 ミュンヘン大学(LMU)
◆研究チームは、好中球が免疫応答の非常に早い段階でアラーミンと呼ばれる特定のメッセンジャーを放出する分子メカニズムを発見しました。このアラーミンは、NLRP3インフラマソームの活性化によって好中球の細胞膜内のガスデルミンD孔を通じて放出されます。このプロセスは非常に迅速で可逆的であり、炎症プロセスを早い段階で治療的に調整できる可能性を開きます。
<関連情報>
- https://www.lmu.de/en/newsroom/news-overview/news/immune-system-mechanisms-of-alarmin-release-discovered.html
- https://www.nature.com/articles/s41590-023-01656-1
E-セレクチンを介した迅速なNLRP3インフラマソーム活性化は、一過性のガスダミンD孔形成を介した好中球からのS100A8/S100A9放出を制御する E-selectin-mediated rapid NLRP3 inflammasome activation regulates S100A8/S100A9 release from neutrophils via transient gasdermin D pore formation
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
Nature Immunology Published:30 October 2023
DOI:https://doi.org/10.1038/s41590-023-01656-1
Abstract
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 KV1.3 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.
