Why should the molecular characterization of inflammasome-induced exosomal cargo be done?

Abstract

Exosomes (EXSs) are nano-sized and circulat ing membrane-bound extracellular vesicles (EVs) which protect the stability of their cargo, including messenger ribonucleic acid (mRNA), microRNA (miRNA) and other proteins from degradation. Upon taken up by recipient cells, they deliver their cargo molecules to the target cells. When inflammatory stimuli activate innate immune signaling receptors, cargo molecules modify the molecules of recipient cell. Because molecules carried with EXS-cargo are thought to be biomarkers, the role of EXSs is emerging as an important new area of biomedical research. In addition to inflammatory mediators, EXSs, which are secreted by macrophages play pivotal roles in intercellular communications and multi biological functions (1). The immune response-related proteins and signaling pathways are specifically enriched in inflammasome-derived EXSs. This type of EXSs directly activates nuclear factor kappa B (NF-κB) signaling pathway and expresses pro-interleukin 1-beta (pro-IL-1β) and pro-IL-18 via its transcriptional upregulation (2). EXSs as potential carriers for targeted gene, are thought to promote inflammation via releasing of inflammasome components during the inflammatory response. Of note, there is a need for further studies to elucidate the role of EXSs by using improved detection and characterization methods (3). Indeed, inflammasomes are critical for both local and systemic inflammation. Canonical type NODlike receptor protein 3 (NLRP3) inflammasome is known to sense multiple microbial and endogenous danger signals, and its activation results in caspase-1, IL-1β and IL-18, dependent processes. However, non-canonical, caspase4/5-dependent inflammasomes bind to intracellular lipopolysaccharides (LPS), and directly regulate pyroptosis (4,5). Contrarily, Budden et al. have proposed that the pathways eliciting caspase 1-driven cell death strongly induce EXS release, whereas stimuli, which do not induce pyroptosis are weaker stimuli for EXS release (6). In this context two noteworthy results are emerged in this study. EXSs released from inflammasome-activated macrophages have a specific RNA signature and contain interferonbeta (IFN-β). IFN-β is responsible for the induction of IFN-stimulated genes (ISGs) in EXS recipient cells, independently of NLRP3 expression. Thereby, this cargo induces an IFN signature in bystander cells and leads to silencing of NLRP3 inflammasome response (6). In this situation, IFN-β inhibits NLRP3 inflammasomes in a signal transducer and activator of transcription 1 (STAT1)dependent manner, while decreases the amounts of pro-IL1β in a STAT3-dependent manner (7). In case of toll-like receptor (TLR) activation, Toll/IL-1 receptor homology (TIR)-domain-containing adaptor protein-inducing IFN-β (TRIF) interacts with receptor-interacting protein 1 (RIP1), which is responsible for the activation of NFκB. Thus, stimulation with TLR ligands induces type I IFN production in addition to proinflammatory signals via TRIF-dependent pathway (8). However, activation of inflammasome controls the post-translational proteolytic activity of IL-1β, IL-18, pore-forming gasdermins and caspase-1. Pyroptosis commonly occurs with the activation of the caspase-1-dependent canonical pathway and the Editorial Commentary