Date of this Version
Yizhu Lu, Inhibitory Effects of Shiitake-derived Exosome-like Nanoparticles On NLRP3 Inflammasome Activation. MS Thesis., Department of Nutrition and Health Sciences, university of Nebraska-Lincoln, 2019.
The NLRP3 inflammasome is a critical mediator of inflammation and consists of the sensor NOD-like receptor family, pyrin domain containing 3 (NLRP3), the adaptor apoptotic speck protein containing a caspase recruitment domain (ASC), and the effector caspase-1. Dysregulated or excessive activation of the NLRP3 inflammasome contributes to pathogenesis of diverse inflammatory diseases such as Type 2 diabetes and atherosclerosis. Therefore, the NLRP3 inflammasome is a promising therapeutic target for treating these diseases. Extracellular vesicles (EVs) are membrane-enclosed tiny particles released by almost any type of cells and they are involved in the intercellular communication by transferring their cargos including RNAs, proteins, and lipids to target cells. Based on their sizes, origins, and biological functions, EVs are mainly classified into exosomes, microvesicles and apoptotic bodies. Recently, exosome-like nanoparticles (ELNs) have been isolated from some edible plants, and their beneficial effects on diseases have also been reported. Given that mushrooms have been utilized as medicines for long time in some countries and they have anti-cancer, anti-inflammation and anti-microbial properties, we isolated ELNs from six mushrooms and tested their effects on the NLRP3 inflammasome activation. Among these six mushroom-derived ELNs, shiitake-derived ELNs (S-ELNs) significantly suppressed NLRP3 inflammasome activation and therefore were chosen for further study. S-ELNs were nanoparticles that contained RNAs, proteins, and lipids. RNA-labeled S-ELNs or lipid-labeled S-ELNs were taken up by macrophages in a dose-dependent manner. S-ELNs had a broad inhibitory effect on the NLRP3 inflammasome activated by FFA, alum, nigericin, and ATP. S-ELNs inhibited assembly of the NLRP3 inflammasome. Importantly, we further identified lipids in S-ELNs lipids as active biomolecules that play an important role in suppressing NLRP3 inflammasome activation. Taken together, our findings suggested that S-ELNs is a promising agent that suppresses NLRP3 inflammasome activation.
Advisor: Jiujiu Yu