The NLRP3-Caspase 1 Inflammasome Negatively Regulates Autophagy via TLR4-TRIF in Prion Peptide-Infected Microglia

Abstract

Prion diseases are neurodegenerative disorders characterized by the accumulation of misfolded prion protein, spongiform changes in the brain, and brain inflammation as a result of the wide-spread activation of microglia. Autophagy is a highly conserved catabolic process for the clearance of cytoplasmic components, including protein aggregates and damaged organelles; this process also eliminates pathological PrPSc as it accumulates during prion infection. The NALP3 inflammasome is a multiprotein complex that is a component of the innate immune system and is responsible for the release of pro-inflammatory cytokines. Our previous study showed that the neurotoxic prion peptide PrP106-126 induces NALP3 inflammasome activation and subsequent IL-1β release in microglia. Autophagy is involved in the regulation of the immune responses and inflammation in many diseases including neurodegenerative diseases. However, the relationship between autophagy and NALP3 inflammasome in prion diseases has not been investigated. In this study, we demonstrated that the processing and release of mature IL-1β is significantly enhanced by the inhibition of autophagy. Conversely, gene-silencing of the NALP3 inflammasome promotes autophagy. Suppression of TRIF or TLR4 by siRNA attenuated PrP106-126-induced autophagy, which is indicating that the TLR4-TRIF signaling pathway is involved in PrP106-26-induced autophagy. Caspase 1 directly cleaved TRIF to diminish TLR-4-TRIF mediated autophagy. Our findings suggest that the inhibition of autophagy by NALP3 inflammasome is probably mediated by activated Caspase-1-induced TRIF cleavage. This is the first study reporting that the NALP3 inflammasome complex negatively regulates autophagy in response to PrP106-126 stimulation in microglia, and partly explains the mechanism of autophagy inhibition by Caspase-1 in PrP106-126-induced BV2 cell activation. Our findings suggest that autophagy up-regulation and inhibition of Caspase-1 may protect against prion-induced neuroinflammation and accelerate misfolded protein degradation and are potential therapeutic approaches for prion diseases.

Inflammasomes in neuroinflammatory and neurodegenerative diseases

“…Stimulation of microglia with PrP fibrils was also shown to induce toxicity in neurons (Hafner-Bratkovi c et al, 2012). Mechanistically, NLRP3 inflammasome activation was suggested to negatively regulate autophagy in microglia, thereby contributing to neurodegeneration (Lai et al, 2018). Inhibition of IL-1R signaling with anakinra was shown to reduce seizure susceptibility in a CJD mouse model (Bertani et al, 2017).…”

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…As second signals, adenine triphosphate (ATP), misfolded proteins, crystalline substances, pore‐forming toxins, particulate matter, and viral RNA are the most common inducers of NLRP3 inflammasome activation . In neurodegenerative disorders, microglial NLRP3 inflammasome becomes activated by sensing different endogenous signals or proteins, such as amyloid‐β, α‐synuclein, superoxide dismutase, prion protein, ATP, and members of the complement pathways . In addition, several other exogenous stimuli or environmental toxins have been found to be responsible for producing neuronal damage by disrupting mitochondrial and lysosomal function and by producing ROS and other proteinaceous insults in PD .…”

Autophagy and Cell Death in Alzheimer’s, Parkinson’s and Prion Diseases

“…An efficient autophagy (AUT) delays or attenuates the progression of AD, PD and PrD [9][10][11][12]. A summary of AUT changes in selected NBD is shown in Figure 2.…”

“…Activated inflammasomes lead to a low-grade inflammation associated with a declined autophagic capacity [59]. On the other hand, autophagy attenuation leads to inflammasome precipitated excessive caspase-1 activation and elevated IL-1β secretion in response to lipopolysaccharide (LPS) stimulation [10,60,61]. Also, ER stress and inflammation coexist in NBD, for example, in AD, and are intertwined [57].…”