scholarly journals Regulation of the NLRP3 Inflammasome by Post-Translational Modifications and Small Molecules

2021 ◽  
Vol 11 ◽  
Author(s):  
Jin Kyung Seok ◽  
Han Chang Kang ◽  
Yong-Yeon Cho ◽  
Hye Suk Lee ◽  
Joo Young Lee
Keyword(s):  
Small Molecules ◽  
Nlrp3 Inflammasome ◽  
Intracellular Signaling ◽  
Defense Mechanism ◽  
Therapeutic Strategies ◽  
The Body ◽  
Inflammasome Activation ◽  
Post Translational Modifications ◽  
Nlrp3 Inflammasome Activation ◽  
Molecular Patterns

Inflammation is a host protection mechanism that eliminates invasive pathogens from the body. However, chronic inflammation, which occurs repeatedly and continuously over a long period, can directly damage tissues and cause various inflammatory and autoimmune diseases. Pattern recognition receptors (PRRs) respond to exogenous infectious agents called pathogen-associated molecular patterns and endogenous danger signals called danger-associated molecular patterns. Among PRRs, recent advancements in studies of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome have established its significant contribution to the pathology of various inflammatory diseases, including metabolic disorders, immune diseases, cardiovascular diseases, and cancer. The regulation of NLRP3 activation is now considered to be important for the development of potential therapeutic strategies. To this end, there is a need to elucidate the regulatory mechanism of NLRP3 inflammasome activation by multiple signaling pathways, post-translational modifications, and cellular organelles. In this review, we discuss the intracellular signaling events, post-translational modifications, small molecules, and phytochemicals participating in the regulation of NLRP3 inflammasome activation. Understanding how intracellular events and small molecule inhibitors regulate NLRP3 inflammasome activation will provide crucial information for elucidating the associated host defense mechanism and the development of efficient therapeutic strategies for chronic diseases.

scholarly journals The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1219 ◽  
Author(s):  
Yang Zhou ◽  
Zhizi Tong ◽  
Songhong Jiang ◽  
Wenyan Zheng ◽  
Jianjun Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Immune Defense ◽  
Inflammasome Activation ◽  
Nucleotide Binding Domain ◽  
Cholesterol Trafficking ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Molecular Patterns

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.

scholarly journals Distinct Molecular Mechanisms Underlying Potassium Efflux for NLRP3 Inflammasome Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Ziwei Xu ◽  
Zi-mo Chen ◽  
Xiaoyan Wu ◽  
Linjie Zhang ◽  
Ying Cao ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Inflammasome Activation ◽  
Potassium Efflux ◽  
Pannexin 1 ◽  
Nlrp3 Inflammasome Activation ◽  
K2p Channels ◽  
Pore Forming Proteins ◽  
Molecular Patterns

The NLRP3 inflammasome is a core component of innate immunity, and dysregulation of NLRP3 inflammasome involves developing autoimmune, metabolic, and neurodegenerative diseases. Potassium efflux has been reported to be essential for NLRP3 inflammasome activation by structurally diverse pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Thus, the molecular mechanisms underlying potassium efflux to activate NLRP3 inflammasome are under extensive investigation. Here, we review current knowledge about the distinction channels or pore-forming proteins underlying potassium efflux for NLRP3 inflammasome activation with canonical/non-canonical signaling or following caspase-8 induced pyroptosis. Ion channels and pore-forming proteins, including P2X7 receptor, Gasdermin D, pannexin-1, and K2P channels involved present viable therapeutic targets for NLRP3 inflammasome related diseases.

scholarly journals K + Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria

Immunity ◽  
2016 ◽  
Vol 45 (4) ◽  
pp. 761-773 ◽  
Author(s):  
Christina J. Groß ◽  
Ritu Mishra ◽  
Katharina S. Schneider ◽  
Guillaume Médard ◽  
Jennifer Wettmarshausen ◽  
...  
Keyword(s):  
Small Molecules ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation

2019 ◽  
Vol 20 (13) ◽  
pp. 3328 ◽  
Author(s):  
Nathan Kelley ◽  
Devon Jeltema ◽  
Yanhui Duan ◽  
Yuan He
Keyword(s):  
Nlrp3 Inflammasome ◽  
Cellular Damage ◽  
Inflammasome Activation ◽  
Microbial Infection ◽  
Ionic Flux ◽  
Post Translational Modifications ◽  
Cellular Events ◽  
Nlrp3 Inflammasome Activation ◽  
Signaling Events ◽  
Multiple Signaling

The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. However, the aberrant activation of the NLRP3 inflammasome has been linked with several inflammatory disorders, which include cryopyrin-associated periodic syndromes, Alzheimer’s disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, and multiple molecular and cellular events, including ionic flux, mitochondrial dysfunction, and the production of reactive oxygen species, and lysosomal damage have been shown to trigger its activation. How NLRP3 responds to those signaling events and initiates the assembly of the NLRP3 inflammasome is not fully understood. In this review, we summarize our current understanding of the mechanisms of NLRP3 inflammasome activation by multiple signaling events, and its regulation by post-translational modifications and interacting partners of NLRP3.

Human NLRP3 inflammasome activation is Nox1-4 independent

Blood ◽  
2010 ◽  
Vol 115 (26) ◽  
pp. 5398-5400 ◽  
Author(s):  
Robin van Bruggen ◽  
M. Yavuz Köker ◽  
Machiel Jansen ◽  
Michel van Houdt ◽  
Dirk Roos ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Nlrp3 Inflammasome ◽  
Interleukin 1 ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Granulomatous Disease ◽  
Primary Cells ◽  
Proteolytic Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Molecular Patterns

Abstract The NLRP3 inflammasome can be activated by pathogen-associated molecular patterns or endogenous danger-associated molecular patterns. The activation of the NLRP3 inflammasome results in proteolytic activation and secretion of cytokines of the interleukin-1 (IL-1) family. The precise mode of activation of the NLRP3 inflammasome is still elusive, but has been postulated to be mediated by reactive oxygen species (ROS) generated by an NADPH oxidase. Using primary cells from chronic granulomatous disease (CGD) patients lacking expression of p22phox, a protein that is required for the function of Nox1-4, we show that cells lacking NADPH oxidase activity are capable of secreting normal amounts of IL-1β. Thus, we provide evidence that activation of the NLRP3 inflammasome does not depend on ROS generated from an NADPH oxidase.

scholarly journals NLRP3 Inflammasome Activation in Hemodialysis and Hypertensive Patients with Intact Kidney Function

Toxins ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 675
Author(s):  
Christof Ulrich ◽  
Susann Wildgrube ◽  
Roman Fiedler ◽  
Eric Seibert ◽  
Leonie Kneser ◽  
...  
Keyword(s):  
Kidney Function ◽  
Nlrp3 Inflammasome ◽  
Ex Vivo ◽  
The Body ◽  
Inflammasome Activation ◽  
Hypertensive Patients ◽  
Caspase 1 ◽  
Inflammatory Status ◽  
Nlrp3 Inflammasome Activation ◽  
Intact Kidney

Hypertension is not only an integrative characteristic of hemodialysis (HD) patients but is also very common in the general population. There is evidence that the inflammatory cytokine IL-β, regulated by the NLRP3 inflammasome via caspase-1, contributes to the hypertensive setting. Therefore, we investigated in an observational pilot study whether IL-1β secretion and inflammatory cell death (pyroptosis) are different in HD and hypertensive patients with intact kidney function. Twenty HD patients were age-, gender-, and diabetes-mellitus-matched to patients with hypertension and intact kidney function. Caspase-1 activity and pyroptosis rates were measured by flow cytometry. IL-1β was determined by qPCR and the ELISA technique. The inflammatory status (CRP) did not differ between both groups; however, the body mass index, a classical cardiovascular risk factor, was significantly elevated in blood pressure (BP) patients. BP patients had a higher frequency of caspase-1-positive monocytes compared to HD (p < 0.001). IL1-β protein secretion was significantly enhanced in BP, but ex vivo stimulation of blood cells resulted in higher pyroptosis rates in HD compared to BP patients (p < 0.01). Therefore, HD and BP patients differ in the extent of the NLRP3 inflammasome activation. The consequences of overweight, present in BP patients, may contribute to the significantly higher inflammasomal induction level. Whether low pyroptotic rates are equivalent to a dysfunctional immune response or a high pyroptotic output corresponds to over-activation remains to be clarified.

scholarly journals NLRP3 Ubiquitination—A New Approach to Target NLRP3 Inflammasome Activation

2021 ◽  
Vol 22 (16) ◽  
pp. 8780
Author(s):  
Mahbuba Akther ◽  
Md Ezazul Haque ◽  
Jooho Park ◽  
Tae-Bong Kang ◽  
Kwang-Ho Lee
Keyword(s):  
Nlrp3 Inflammasome ◽  
Critical Event ◽  
Inflammasome Activation ◽  
Activation Process ◽  
Post Translational Modifications ◽  
Inflammatory Disorders ◽  
Pyrin Domain ◽  
Cellular Events ◽  
Nlrp3 Inflammasome Activation ◽  
Wide Range

In response to diverse pathogenic and danger signals, the cytosolic activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing (3)) inflammasome complex is a critical event in the maturation and release of some inflammatory cytokines in the state of an inflammatory response. After activation of the NLRP3 inflammasome, a series of cellular events occurs, including caspase 1-mediated proteolytic cleavage and maturation of the IL-1β and IL-18, followed by pyroptotic cell death. Therefore, the NLRP3 inflammasome has become a prime target for the resolution of many inflammatory disorders. Since NLRP3 inflammasome activation can be triggered by a wide range of stimuli and the activation process occurs in a complex, it is difficult to target the NLRP3 inflammasome. During the activation process, various post-translational modifications (PTM) of the NLRP3 protein are required to form a complex with other components. The regulation of ubiquitination and deubiquitination of NLRP3 has emerged as a potential therapeutic target for NLRP3 inflammasome-associated inflammatory disorders. In this review, we discuss the ubiquitination and deubiquitination system for NLRP3 inflammasome activation and the inhibitors that can be used as potential therapeutic agents to modulate the activation of the NLRP3 inflammasome.

scholarly journals Vitamin D and the NLRP3 Inflammasome

2020 ◽  
Vol 10 (23) ◽  
pp. 8462
Author(s):  
Matthew Tunbridge ◽  
Pedro Henrique França Gois
Keyword(s):  
Vitamin D ◽  
Nlrp3 Inflammasome ◽  
Clinical Evidence ◽  
The Body ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Nucleotide Binding Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Improved Outcomes

Vitamin D (VD) is a steroid hormone classically known for its key role in maintaining calcium homeostasis in the body. VD also has important immunomodulatory functions. This review explores evidence for a role of VD in attenuating the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Dysregulated and inappropriate NLRP3 inflammasome activation occurs in a range of human diseases, including autoinflammatory disorders, metabolic disorders, and infections. VD appears to mediate its effects by binding of the VD receptor (VDR) to the sensor protein NLRP3, inhibiting deubiquitination and downstream inflammasome assembly. Some early clinical evidence suggests improved outcomes in inflammasome-mediated disorders when VD-deficient patients are treated with supplementation therapy.

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