Year: 2026
Type: article
Abstract: The NLRP3 inflammasome contributes to a wide range of conditions from infections to Alzheimer’s disease. NLRP3 forms an inactive decameric cage, that upon interaction with the trans-Golgi network (TGN) and microtubule organization center (MTOC), leads to inflammasome activation, yet whether non-decamer NLRP3 species form functional inflammasomes remains unclear. Here, we design a NLRP3 exon 3 deletion variant that forms low molecular weight NLRP3 assemblies. Spatially and dynamically highly resolved microscopy in THP-1 and human macrophages shows that nigericin, a K + -dependent NLRP3 stimulus, can trigger two distinct activation pathways: (i) the rapidly engaged decameric cage-dependent pathway; and (ii) a decameric cage-independent, TGN/MTOC-distal, and slow-reacting pathway employed by low molecular weight NLRP3 species, that dominates in human neutrophils. Collectively, our results delineate two parallel yet biologically distinct NLRP3 activation pathways, thereby providing a framework to understand NLRP3-driven inflammation across a wide range of pathological context and cell types.
Source: Nature Communications
Institutions: University of Tübingen, University of Bonn, University Hospital Bonn, Hertie Institute for Clinical Brain Research, Centre National de la Recherche Scientifique, Institut National des Sciences Appliquées de Toulouse, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Université de Toulouse, Deutsches Konsortium für Translationale Krebsforschung, Santa Lucía University General Hospital, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Ministerio de Ciencia, Innovación y Universidades, Deutsche Forschungsgemeinschaft, Volkswagen Foundation, Eberhard Karls Universität Tübingen, Universidad de Murcia, Universitetet i Oslo, Uppsala Universitet, Association Neurofibromatoses et Recklinghause, Agencia Estatal de Investigación, European Social Fund
OpenAlex ID: W7162767473