Interplay Between NLRP3 Inflammasome and Autophagy

Abstract

The NLRP3 inflammasome is cytosolic multi-protein complex that induces inflammation and pyroptotic cell death in response to both pathogen (PAMPs) and endogenous activators (DAMPs). Recognition of PAMPs or DAMPs leads to formation of the inflammasome complex, which results in activation of caspase-1, followed by cleavage and release of pro-inflammatory cytokines. Excessive activation of NLRP3 inflammasome can contribute to development of inflammatory diseases and cancer. Autophagy is vital intracellular process for recycling and removal of damaged proteins and organelles, as well as destruction of intracellular pathogens. Cytosolic components are sequestered in a double-membrane vesicle—autophagosome, which then fuses with lysosome resulting in degradation of the cargo. The autophagy dysfunction can lead to diseases with hyperinflammation and excessive activation of NLRP3 inflammasome and thus acts as a major regulator of inflammasomes. Autophagic removal of NLRP3 inflammasome activators, such as intracellular DAMPs, NLRP3 inflammasome components, and cytokines can reduce inflammasome activation and inflammatory response. Likewise, inflammasome signaling pathways can regulate autophagic process necessary for balance between required host defense inflammatory response and prevention of excessive and detrimental inflammation. Autophagy has a protective role in some inflammatory diseases associated with NLRP3 inflammasome, including gouty arthritis, familial Mediterranean fever (FMF), and sepsis. Understanding the interregulation between these two essential biological processes is necessary to comprehend the biological mechanisms and designing possible treatments for multiple inflammatory diseases.

Dengue Virus Envelope Protein Domain III Induces Nlrp3 Inflammasome-Dependent NETosis-Mediated Inflammation in Mice

“…Inflammasomes regulate and interact with various RCDs ( 72 , 76 – 78 ). The inhibitors of either Nlrp3 inflammasome/pyroptosis (inhibitor OLT1177) or NETosis (inhibitor GSK484) can suppress to each other ( Figure 4 ), suggests there could exist a cross-talk between these 2 pathways.…”

The P2X7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis

“…Numerous studies highlight interactions between autophagy and the NLRP3 inflammasome (Biasizzo and Kopitar-Jerala, 2020 ); while the specific role of the P2X 7 receptor is usually not involved, autophagic degradation of inflammasome components is predicted to regulate the ability of the P2X 7 receptor to activate the NLRP3 inflammasome. Increased autophagy is associated with decreased NLRP3 inflammasome function in vivo in rodent microglial cells (Chen et al, 2019 ), and in primary microglia cells (Cho et al, 2014 ; Chen et al, 2019 ; Han et al, 2019 ).…”

Outer membrane vesicles produced by pathogenic strains ofEscherichia coliblock autophagic flux and exacerbate inflammasome activation

“…Numerous studies showed that autophagy is a negative regulator that prevents excessive activation of inflammasomes (Biasizzo and Kopitar-Jerala, 2020; Deretic et al, 2013; Harris et al, 2017; Krakauer, 2019; Netea-Maier et al, 2015; Qian et al, 2017). We therefore speculated that OMV-dependent inhibition of autophagic flux could exacerbate inflammasome activation.…”

“…Our results revealed that these OMVs inhibit the autophagic flux and are much more prone to overactivate the non-canonical inflammasome pathway, the main host defense mechanism against infections that must be tightly regulated to ensure a correct antimicrobial response. Autophagy is one of the main negative regulator of inflammasome activation and plays a protective role in inflammatory diseases such as sepsis (Biasizzo and Kopitar-Jerala, 2020; Feng et al, 2019; Ho et al, 2016; Qiu et al, 2019). Thus, these OMVs, produced by bacteria responsible of extraintestinal infections, could destabilize the host response to the infection, thus facilitating its progression.…”