Neurodegenerative Disease and the NLRP3 Inflammasome

Holbrook, Jonathan; Jarosz-Griffiths, Heledd; Caseley, Emily A.; Lara-Reyna, Samuel; Poulter, James A.; Williams‐Gray, Caroline H.; Peckham, Daniel; McDermott, Michael F.

doi:10.3389/fphar.2021.643254

Cited by 136 publications

(92 citation statements)

References 200 publications

(230 reference statements)

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“…There are several neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) where NLRP3 mediated chronic inflammation plays a crucial role in the pathological progression (Tan et al, 2013;Cho et al, 2014). Downregulation of autophagy has also been implicated in both AD and PD pathology, where it leads to reduced clearance of amyloid beta and alpha synuclein (Wani et al, 2019;Holbrook et al, 2021;Wani et al, 2021). Therefore, compounds like IIIM-941, which have the potential to target both inflammation and autophagy can raise new hope for the treatment of these diseases.…”

Section: Discussionmentioning

confidence: 99%

IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy

et al. 2021

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Aberrant activation of NLRP3 inflammasome has been implicated in several inflammatory diseases. Autophagy is one of the primary mechanisms that regulate NLRP3 inflammasome activity. In this study, we attempted to target NLRP3 inflammasome activity by a synthetic compound IIIM-941. We found that IIIM-941 inhibits ATP induced NLRP3 inflammasome by induction of autophagy through AMPK pathway in bone marrow derived macrophages (BMDMs) and J774A.1 cells. It was interesting to observe that IIIM-941 did not show any inhibitory activity against LPS induced pro-inflammatory cytokines TNF-α and IL-6. The anti-NLRP3 activity of IIIM-941 was significantly reversed when we attempted to block autophagy by using either pharmacological inhibitor bafilomycin A1or by using siRNA against AMPK. Further, we found that IIIM-941 downregulated the expression of NLRP3 and prevented the oligomerization of ASC to exert its anti-NLRP3 inflammasome effect in J774A.1 cells. We validated inhibitory activity of IIIM-941 against NLRP3 in three different mice models. The anti-inflammatory effect of IIIM-941 was highly significant in ATP induced peritoneal inflammation model. IIIM-941 was similarly effective in suppressing MSU induced IL-1β in the air pouch model of inflammation without affecting the levels of TNF-α and IL-6. Finally, oral efficacy of IIIM-941 was also proved in MSU indued foot paw edema model of inflammation in mice at 10 and 20 mg/kg (b.w.). The compounds like IIIM-941 can be explored further for the development of therapies against diseases such as Alzheimer’s disease and Parkinson’s disease, where hampered autophagy and NLRP3 activation play a crucial role in the pathological development.

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Section: Discussionmentioning

confidence: 99%

IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy

et al. 2021

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“…Currently, pyroptosis has been proved to be related with pathogenesis of inflammatory, metabolic diseases, neurodegenerative diseases [ 16 , 81 , 83 , 84 ]. Inflammasome is a multiprotein complex involved in the innate immune system, causing inflammatory responses and pyroptosis.…”

Section: Pyroptosismentioning

confidence: 99%

Regulated cell death: discovery, features and implications for neurodegenerative diseases

Cui

Zhao

et al. 2021

Cell Commun Signal

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Regulated cell death (RCD) is a ubiquitous process in living organisms that is essential for tissue homeostasis or to restore biological balance under stress. Over the decades, various forms of RCD have been reported and are increasingly being found to involve in human pathologies and clinical outcomes. We focus on five high-profile forms of RCD, including apoptosis, pyroptosis, autophagy-dependent cell death, necroptosis and ferroptosis. Cumulative evidence supports that not only they have different features and various pathways, but also there are extensive cross-talks between modes of cell death. As the understanding of RCD pathway in evolution, development, physiology and disease continues to improve. Here we review an updated classification of RCD on the discovery and features of processes. The prominent focus will be placed on key mechanisms of RCD and its critical role in neurodegenerative disease. Graphical Abstract

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“…In the last 20 years, several inflammasomes have been identified [ 38 ]; however, the currently most characterized one is the NLRP3 (NOD-like receptor protein 3) intracellular inflammasome, which belongs to the NOD-like receptor (NLR) family. It is activated in response to several signals and plays an important role in inflammatory diseases, autoimmune diseases, metabolic diseases (metabolic syndrome, obesity, diabetes, and gout), cardiovascular diseases, neurodegenerative diseases (Parkinson’s and Alzheimer’s disease), multiple sclerosis, and also in psychiatric diseases [ 39 , 40 , 41 , 42 ].…”

Section: Autoinflammatory Disease: Since the Beginning Of ’90s A New Branch Of Medicinementioning

confidence: 99%

Autoinflammatory Diseases and Cytokine Storms—Imbalances of Innate and Adaptative Immunity

Marcuzzi

Melloni

Zauli

et al. 2021

IJMS

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Innate and adaptive immune responses have a well-known link and represent the distinctive origins of several diseases, many of which may be the consequence of the loss of balance between these two responses. Indeed, autoinflammation and autoimmunity represent the two extremes of a continuous spectrum of pathologic conditions with numerous overlaps in different pathologies. A common characteristic of these dysregulations is represented by hyperinflammation, which is an exaggerated response of the immune system, especially involving white blood cells, macrophages, and inflammasome activation with the hyperproduction of cytokines in response to various triggering stimuli. Moreover, hyperinflammation is of great interest, as it is one of the main manifestations of COVID-19 infection, and the cytokine storm and its most important components are the targets of the pharmacological treatments used to combat COVID-19 damage. In this context, the purpose of our review is to provide a focus on the pathogenesis of autoinflammation and, in particular, of hyperinflammation in order to generate insights for the identification of new therapeutic targets and strategies.

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Neurodegenerative Disease and the NLRP3 Inflammasome

Cited by 136 publications

References 200 publications

IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy

IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy

Regulated cell death: discovery, features and implications for neurodegenerative diseases

Autoinflammatory Diseases and Cytokine Storms—Imbalances of Innate and Adaptative Immunity

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