Exogenous nanoparticles and endogenous crystalline molecules as danger signals for the NLRP3 inflammasomes

Abstract

Inflammasome mechanisms are involved as some of the pathways of sterile inflammation. Inflammasomes are large multiprotein complexes in the cytosol and are a key system for the production of the pivotal inflammatory cytokines, interleukin (IL)-1β and IL-18, and inflammatory cell death called pyroptosis. Although a number of inflammasomes have been described, the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) is the most extensively investigated inflammasome. Exogenous pathogen-associated molecular patterns released during infection and endogenous crystalline danger/damage-associated molecular patterns (DAMPs) are well-known activators of NLRP3 inflammasomes. In addition, nanoparticle-associated molecular patterns (NAMPs), which are mediated by synthetic materials, including nanomaterials and nanoparticles, are proposed to be new danger signals of NLRP3 inflammasomes. Importantly, NAMP-and DAMPtriggered inflammation, a defining characteristic in inflammatory diseases, is termed as sterile inflammation because it occurs in the absence of foreign pathogens. This review focuses on the role of inflammasomes in exogenous NAMP-and endogenous crystalline DAMP-mediated sterile inflammation. Moreover, many regulatory mechanisms have been identified to attenuate NLRP3 inflammasomes. Therefore, we also summarize endogenous negative regulators of NLRP3 inflammasome activation, particularly induced by NAMPs or crystalline DAMPs.

Nanoparticles and danger signals: Oral delivery vehicles as potential disruptors of intestinal barrier homeostasis

“…Gallo and Gallucci, 2013, first alluded to the idea of NP‐associated molecular patterns (NAMPs) as studies demonstrated that NPs could be recognized by immune cells, a concept that continues to be supported by a growing body of evidence . As previously mentioned in this review, NPs have been shown to directly bind SRs on macrophages, both class A and class B, inducing phagocytosis and/or NLRP3 inflammasome activation.…”

“…Exposure to NPs has been shown to cause release of various endogenous danger signals—some as a result of oxidative damage and mitochondrial dysfunction, others as a result of lysosomal rupture. Whereas apoptosis is a common fate of cells exposed to NPs, other more inflammatory forms of cell death have been shown to occur as well; NP‐induced release of mitochondrial and lysosomal DAMPs can trigger a highly inflammatory mode of cell death termed pyroptosis, whereas disruption in the cell membrane through either direct cell‐NP interactions or through oxidative damage can lead to necrosis . In this way, DAMPs produced as a result of NP exposure can be released into the extracellular compartment following cell death via pyroptotic or necrotic pathways, acting as endogenous danger signals to nearby cells.…”

“…The role of NPs in the activation of this canonic pathway, as previously mentioned, is largely due to their ability to up‐regulate expression of inflammasome components, as well as produce activation signals via oxidative damage (i.e., mtDNA and ATP) or cathepsin B release. Both pathways, however, lead to the cleavage of the pore‐forming protein gasdermin D, which itself is a protease and is the ultimate cause of the pyroptotic cell death through pore formation in the membrane and subsequent loss of osmotic potential . Once osmotic potential is lost, the cell swells and ruptures, releasing DAMPs and proinflammatory mediators.…”

“…Once osmotic potential is lost, the cell swells and ruptures, releasing DAMPs and proinflammatory mediators. For a more recent in‐depth review of these specific processes, which includes activation by NPs, see Shirasuna et al., 2018 …”

“…This is dependent on different classes of NPs—such as transition metal oxides, soluble metal oxides, cationic/anionic liposomes, and others— as well as size, added particle coatings, and functional groups, crystalline vs. amorphous structure, and acquired biocoronas . Recent studies are shedding more light on exactly how these different chemical compositions interact with cells and subcellular components, with evidence suggesting that responses may not only be NP‐specific, but also cell‐type specific …”