Targeting the NLRP3 inflammasome as new therapeutic avenue for inflammatory bowel disease

Chen, Qiuling; Yin, Hao-Ran; He, Qing‐Yu; Wang, Ying

doi:10.1016/j.biopha.2021.111442

Cited by 70 publications

(50 citation statements)

References 105 publications

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“…Colitis is a well-known inflammatory disease which triggers severe inflammation in the intestine. Excessive ROS production and the activation of the NLRP3 inflammasome is accompanied by the upregulation interleukin (IL)-1β and IL-18 [ 31 , 32 ]. As colitis is associated with activation of the NLRP3 inflammasome, we used ATP- or DSS-activated macrophages to examine the interaction between Rubicon and p22phox in vitro.…”

Section: Resultsmentioning

confidence: 99%

Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice

Kim

Jang

et al. 2021

Antioxidants

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The run/cysteine-rich-domain-containing Beclin1-interacting autophagy protein (Rubicon) is essential for the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by interacting with p22phox to trigger the production of reactive oxygen species (ROS) in immune cells. In a previous study, we demonstrated that the interaction of Rubicon with p22phox increases cellular ROS levels. The correlation between Rubicon and mitochondrial ROS (mtROS) is poorly understood. Here, we report that Rubicon interacts with p22phox in the outer mitochondrial membrane in macrophages and patients with human ulcerative colitis. Upon lipopolysaccharide (LPS) activation, the binding of Rubicon to p22phox was elevated, and increased not only cellular ROS levels but also mtROS, with an impairment of mitochondrial complex III and mitochondrial biogenesis in macrophages. Furthermore, increased Rubicon decreases mitochondrial metabolic flux in macrophages. Mito-TIPTP, which is a p22phox inhibitor containing a mitochondrial translocation signal, enhances mitochondrial function by inhibiting the association between Rubicon and p22phox in LPS-primed bone-marrow-derived macrophages (BMDMs) treated with adenosine triphosphate (ATP) or dextran sulfate sodium (DSS). Remarkably, Mito-TIPTP exhibited a therapeutic effect by decreasing mtROS in DSS-induced acute or chronic colitis mouse models. Thus, our findings suggest that Mito-TIPTP is a potential therapeutic agent for colitis by inhibiting the interaction between Rubicon and p22phox to recover mitochondrial function.

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Section: Resultsmentioning

confidence: 99%

Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice

Kim

Jang

et al. 2021

Antioxidants

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“…Although the role of the NLRP3 inflammasome in murine IBD models with NLRP3, ASC, or caspase-1 deficiency remains controversial ( Siegmund et al, 2001 ; Allen et al, 2010 ; Bauer et al, 2010 ; Dupaul-Chicoine et al, 2010 ; Zaki et al, 2010 ; Bauer et al, 2012 ; Mao et al, 2018 ), inhibitors targeting the NLRP3 inflammasome, such as MCC950, oridonin, and INF39, have anti-inflammatory effects in colitis models ( Chen et al, 2021 ). Consistent with previous studies, in an animal colitis model, WT161 improved weight loss and DAI score induced by DSS in this study.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, WT161 exerted protective effects in a DSS-induced murine model. The role of the NLRP3 inflammasome in murine IBD models remains controversial and has been extensively discussed ( Mao et al, 2018 ; Chen et al, 2021 ). Researchers have attempted to analyze and explain this contradiction.…”

Section: Discussionmentioning

confidence: 99%

“…Researchers have indicated that single-nucleotide polymorphisms in the NLRP3 gene are associated with susceptibility to UC ( Hanaei et al, 2018 ; Zhou et al, 2021 ), and NLRP3 inflammasome activity is increased in some patients with UC and Crohn’s disease ( McAlindon et al, 1998 ; Coccia et al, 2012 ). Moreover, selective blockade of the NLRP3 inflammasome could ameliorate colonic inflammation in a colitis model ( Chen et al, 2021 ; Song et al, 2021 ). Thus, the NLRP3 inflammasome may be a promising target for future treatment of IBD.…”

Section: Introductionmentioning

confidence: 99%

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Identification of WT161 as a Potent Agent for the Treatment of Colitis by Targeting the Nucleotide-Binding Domain-Like Receptor Family Pyrin Domain Containing 3 Inflammasome

et al. 2022

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Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis (UC), are chronic and recurrent intestinal inflammatory disorders. Numerous studies have revealed that the nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a pivotal role in the pathogenesis of IBD, and inhibition of the NLRP3 inflammasome alleviates colitis in experimental animals. Our previous study showed that C646, an inhibitor of histone acetyltransferase p300, has a protective role in dextran sulfate sodium (DSS)-induced colitis by targeting the NLRP3 inflammasome, making us further study the inhibitors of histone deacetylases (HDACs) in the treatment of colitis. In this study, we have shown that WT161, an inhibitor of HDAC6, exerts a protective role in a colitis model, blocks NLRP3 inflammasome activation, disrupts ASC speck formation, and decreases the expression of NLRP3. This study uncovers a new inhibitor of the NLRP3 inflammasome and suggests its potential application in the treatment of active IBD.

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“…Hereditary caps such as Muckle–Wells syndrome (MWS), neonatal multi-system inflammatory diseases, and familial cold auto-inflammatory syndrome result from functional acquisition mutations of the NLRP3 inflammasome ( Awad et al, 2019 ; Iida et al, 2019 ; Nair et al, 2019 ). Moreover, NLRP3 inflammasome activation is conducive to the evolution of many other medical conditions, including Parkinson's disease ( Han et al, 2019 ), inflammatory bowel disease ( Chen et al, 2021 ), Alzheimer’s disease ( Feng et al, 2020 ), Crohn’s disease ( Zhang G. et al, 2021 ), and liver disease ( Yang et al, 2020 ). Pharmacological inhibitors of the NLRP3 inflammasome have exhibited significant therapeutic efficacy in multiple animal models ( Daniels et al, 2016 ; Wu et al, 2017 ; Renaudin et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Dihydrotanshinone I Specifically Inhibits NLRP3 Inflammasome Activation and Protects Against Septic Shock In Vivo

et al. 2021

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The abnormal activation of the NLRP3 inflammasome is closely related to the occurrence and development of many inflammatory diseases. Targeting the NLRP3 inflammasome has been considered an efficient therapy to treat infections. We found that dihydrotanshinone I (DHT) specifically blocked the canonical and non-canonical activation of the NLRP3 inflammasome. Nevertheless, DHT had no relation with the activation of AIM2 or the NLRC4 inflammasome. Further study demonstrated that DHT had no influences on potassium efflux, calcium flux, or the production of mitochondrial ROS. We also discovered that DHT suppressed ASC oligomerization induced by NLRP3 agonists, suggesting that DHT inhibited the assembly of the NLRP3 inflammasome. Importantly, DHT possessed a significant therapeutic effect on NLRP3 inflammasome–mediated sepsis in mice. Therefore, our results aimed to clarify DHT as a specific small-molecule inhibitor for the NLRP3 inflammasome and suggested that DHT can be used as a potential drug against NLRP3-mediated diseases.

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Targeting the NLRP3 inflammasome as new therapeutic avenue for inflammatory bowel disease

Cited by 70 publications

References 105 publications

Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice

Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice

Identification of WT161 as a Potent Agent for the Treatment of Colitis by Targeting the Nucleotide-Binding Domain-Like Receptor Family Pyrin Domain Containing 3 Inflammasome

Dihydrotanshinone I Specifically Inhibits NLRP3 Inflammasome Activation and Protects Against Septic Shock In Vivo

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