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A novel and promising NLRP3 inflammasome inhibitor: Dehydroisohispanolone
* 1 , 1 , 2 , 2 , 1 , 3
1  Departamento de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Plaza Ramón y Cajal s/n, 28040 Madrid, Spain
2  Departamento de Química Orgánica, Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, Avda, Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain
3  Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Carretera de Majadahonda-Pozuelo Km 2, 28220 Madrid, Spain
Academic Editor: Alfredo Berzal-Herranz


The NLRP3 inflammasome is a complex present in cells of the innate immune system and involved in numerous inflammatory diseases, being a potential target for their treatment. NLRP3 inflammasome regulates caspase-1 activation and subsequent interleukin (IL)-1β and IL-18 release, and a type of cell death named pyroptosis. However, no specific NLRP3 inhibitors are clinically available to date. Dehydroisohispanolone (DIH) is a natural compound derived from the diterpene hispanolone with anti-inflammatory activity via inhibition of NF-κB activation. In this study, we evaluated whether DIH modulates NLRP3 inflammasome activation in macrophages. Our findings revealed that DIH inhibited NLRP3 activation in J774A.1 macrophages triggered by diverse stimuli (LPS plus nigericin/ adenosine triphosphate/ monosodium urate crystals), as it reduced IL-1β release and caspase-1 activation. DIH treatment also diminished cleaved IL-1β and caspase-1 p10 expression, although expression of NLRP3, ASC, pro-IL-1β and pro-caspase-1 was not affected. Pyroptosis mediated by NLRP3 activation was also attenuated by DIH. In addition, we found that DIH acts as a dual NLRP3 inhibitor by inhibition of LPS-induced priming step in NLRP3 inflammasome activation. Similar results on IL-1β release were observed in nigericin-activated bone marrow-derived macrophages. Covalent molecular docking study of DIH onto the ATP-binding site revealed that DIH binds to NLRP3, forming a covalent bond with Cys415. In conclusion, our experiments show that DIH is an effective NLRP3 inflammasome inhibitor, by inhibiting both the priming and the activation steps, making DIH a promising therapeutic agent for the treatment of inflammatory-related diseases.

Keywords: NLRP3 inflammasome; diterpene; dehydroisohispanolone; interleukin-1β; caspase-1