title: F-actin dampens NLRP3 inflammasome activity via Flightless-I and LRRFIP2.
abstract: NLRP3 and ASC are able to form a large multimeric complex called inflammasome in response to a number danger signals. The NLRP3 inflammasome is required for the activation of caspase-1 and subsequent maturation of pro-IL-1β into active IL-1β. Although the mechanisms regulating the formation and activity of NLRP3 inflammasome are yet not fully elucidated, data suggest that the assembly of NLRP3 inflammasome requires microtubules to induce the proximity of ASC and NLRP3. In this study we show that microfilaments (F-actin) inhibit NLRP3 inflammasome activity and interact with NLRP3 and ASC. We demonstrate that the inhibition depends on the actin polymerization state but not on the active polymerization process. In ATP- or nigericin-activated macrophages, our data further indicate that Flightless-I (FliI) and leucine-rich repeat FliI-interaction protein 2 (LRRFIP2) are required for the co-localization of NLRP3, ASC and F-actin. We also established that the ability of Ca(2+) to accentuate the activity of NLRP3 inflammasome is abrogated in FliI- and LRRFIP2-knockdown macrophages, suggesting that Ca(2+) signaling requires the presence of FliI and LRRFIP2. Accordingly, we observed that Ca(2+)/FliI-dependent severing of F-actin suppresses F-actin/FliI/LRRFIP2-dependent NLRP3 inflammasome inhibition leading to increase IL-1β production. Altogether, our results unveil a new function of F-actin in the regulation of NLRP3 inflammasome activity strengthening the importance of cytoskeleton in the regulation of inflammation.
authors.affiliation: Division of Immunology and Allergy, Inflammation and Allergy Research Group, Hans Wilsdorf Laboratory, Department of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Danielle
authors.initials: D
authors.lastname: Burger
authors.affiliation: Division of Angiology and Hemostasis, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Fickentscher
authors.affiliation: Division of Angiology and Hemostasis, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: de Moerloose
authors.affiliation: Division of Angiology and Hemostasis, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland.
authors.forename: Karim J
authors.initials: KJ
authors.lastname: Brandt
mesh_terms: D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009550:Nigericin / Q000494:pharmacology; D058105:Polymerization / Q000187:drug effects; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000074084:THP-1 Cells; D015534:Trans-Activators
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C098179:FLII protein, human; D058847:Inflammasomes; C120550:LRRFIP2 protein, human; D008840:Microfilament Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D000255:Adenosine Triphosphate; D009550:Nigericin