scholarly journals RelA/MicroRNA-30a/NLRP3 signal axis is involved in rheumatoid arthritis via regulating NLRP3 inflammasome in macrophages

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Qiudong Yang ◽  
Wenhua Zhao ◽  
Yuyi Chen ◽  
Yue Chen ◽  
Jiali Shi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcriptional Regulation ◽  
Nlrp3 Inflammasome ◽  
Joint Inflammation ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Bone Damage ◽  
Post Transcriptional Regulation ◽  
Deficient Mice ◽  
Nlrp3 Expression

AbstractNLRP3 inflammasome plays an important role in the pathogenesis of rheumatoid arthritis (RA). However, the post-transcriptional regulation of NLRP3 expression by miRNA in synovial macrophages is still not well understood. The aim of the study is to elucidate the mechanisms of RA with the focus on miRNAs mediated post-transcriptional regulation of the NLRP3 inflammasome. Here, we used NLRP3-deficient mice (NLRP3KO) to cross with TNFα-transgenic mice (TNFTG) to generate NLRP3KO/TNFTG mice, and compared their joint phenotypes with those of their TNFTG and wild-type (WT) littermates at 5 months of age. In comparison to WT mice, articular bone volume and cartilage area are decreased, whereas inflammed area, eroded surface, ALP+ osteoblast number, TRAP+ osteoclast number, and the areas of RelA+F4/80+, Caspase-1+F4/80+, IL-1β+F4/80+ synoviocytes are increased in the TNFTG mice. Knockout of NLRP3 ameliorates joint inflammation and bone damage in TNFTG mice. Further, in TNFα-primed BMDMs, RelA positively regulates NLRP3 expression, but negatively regulates miR-30a. Additionally, miR-30a negatively mediates NLRP3 expression by directly binding to its 3ʹ UTR, suggesting a miR-30a-mediated feedforward loop acting on NLRP3. Finally, intra-articular injection of AAV-miR-30a inhibits NLRP3 inflammasome activation, reduces joint inflammation, and attenuates bone damage in TNFTG mice. Thus, RelA/miR-30a/NLRP3 signal axis is involved in RA through regulating NLRP3 Inflammasome in macrophages.

IL-37d Negatively Regulates NLRP3 Transcription via Receptor-mediated Pathway and Alleviates DSS-induced Colitis

2020 ◽  
Vol 27 (1) ◽  
pp. 84-93
Author(s):  
Yuan Li ◽  
Hongxia Chu ◽  
Mingsheng Zhao ◽  
Chaoze Li ◽  
Yetong Guan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Transcriptional Profiling ◽  
Inflammasome Activation ◽  
Downstream Effector ◽  
Nlrp3 Inflammasome Activation ◽  
Polymerase Chain ◽  
Underlying Mechanisms ◽  
And Control ◽  
Nlrp3 Expression

Abstract Background Interleukin-37 (IL-37) is a new negative immune regulator. It has 5 splicing forms, IL-37a–e, and most research mainly focuses on IL-37b functions in diverse diseases. Our previous research found that IL-37d inhibits lipopolysaccharide-induced inflammation in endotoxemia through a mechanism different from that of IL-37b. However, whether IL-37d plays a role in colitis and the underlying mechanisms is still obscure. Herein, we identified whether IL-37d regulates NLRP3 inflammasome activity and determined its effect on colitis. Methods NLRP3 inflammasome in macrophages from IL-37d transgenic (IL-37dtg) and control wild type (WT) mice were activated by lipopolysaccharide and adenosine 5′-triphosphate. The expression of NLRP3 inflammasome components and its downstream effector, IL-1β, were detected by real-time polymerase chain reaction, western blot, and ELISA. The models of alum-induced peritonitis and dextran sodium sulfate (DSS)-induced colitis were used to investigate the function of IL-37d on regulating the activity of NLRP3 inflammasome in vivo. Results Our results showed that the activation of NLRP3 inflammasome in macrophage and alum-induced peritonitis was inhibited by IL-37d. Strikingly, IL-37d suppressed NLRP3 expression at the priming step via inhibiting NF-κB activation by transcriptional profiling. Moreover, the recombinant protein IL-37d attenuated NLRP3 inflammasome activation and the production of IL-1β, which could be reversed by IL-1R8 knockdown. Finally, IL-37d transgenic mice resisted DSS-induced acute colitis and NLRP3 inflammasome activation. Conclusion Interleukin-37d inhibits overactivation of the NLRP3 inflammasome through regulating NLRP3 transcription in an IL-1R8 receptor-mediated signaling pathway.

scholarly journals The Synthetic Lignan Secoisolariciresinol Diglucoside Prevents Asbestos-Induced NLRP3 Inflammasome Activation in Murine Macrophages

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Ralph A. Pietrofesa ◽  
Patrick Woodruff ◽  
Wei-Ting Hwang ◽  
Priyal Patel ◽  
Shampa Chatterjee ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Nitrosative Stress ◽  
Antioxidant Properties ◽  
Peritoneal Macrophages ◽  
Inflammasome Activation ◽  
Secoisolariciresinol Diglucoside ◽  
Nlrp3 Inflammasome Activation ◽  
Acute And Chronic Inflammation ◽  
Nlrp3 Expression

Background. The interaction of asbestos with macrophages drives two key processes that are linked to malignancy: (1) the generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and (2) the activation of an inflammation cascade that drives acute and chronic inflammation, with the NLRP3 inflammasome playing a key role. Synthetic secoisolariciresinol diglucoside (SDG), LGM2605, is a nontoxic lignan with anti-inflammatory and antioxidant properties and was evaluated for protection from asbestos in murine peritoneal macrophages (MF).Methods. MFs were exposed to crocidolite asbestos ± LGM2605 given 4 hours prior to exposure and evaluated at various times for NLRP3 expression, secretion of inflammasome-activated cytokines (IL-1βand IL-18), proinflammatory cytokines (IL-6, TNFα, and HMGB1), NF-κB activation, and levels of total nitrates/nitrites.Results. Asbestos induces a significant (p<0.0001) increase in the NLRP3 subunit, release of proinflammatory cytokines, NLRP3-activated cytokines, NF-κB, and levels of nitrates/nitrites. LGM2605 significantly reduced NLRP3 ranging from 40 to 81%, IL-1βby 89–96%, and TNFαby 67–78%, as well as activated NF-κB by 48-49% while decreasing levels of nitrates/nitrites by 85–93%.Conclusions. LGM2605 reduced asbestos-induced NLRP3 expression, proinflammatory cytokine release, NF-κB activation, and nitrosative stress in MFs supporting its possible use in preventing the asbestos-induced inflammatory cascade leading to malignancy.

scholarly journals Chronic TLR Stimulation Controls NLRP3 Inflammasome Activation through IL-10 Mediated Regulation of NLRP3 Expression and Caspase-8 Activation

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Prajwal Gurung ◽  
Bofeng Li ◽  
R. K. Subbarao Malireddi ◽  
Mohamed Lamkanfi ◽  
Terrence L. Geiger ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Nlrp3 Expression

scholarly journals TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ying Qin ◽  
Qi Li ◽  
Wenbo Liang ◽  
Rongzhen Yan ◽  
Li Tong ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Sumo Modification ◽  
Nlrp3 Inflammasome Activation ◽  
Sumo Ligase ◽  
Tripartite Motif ◽  
Nlrp3 Expression

AbstractThe cellular NLRP3 protein level is crucial for assembly and activation of the NLRP3 inflammasome. Various posttranslational modifications (PTMs), including phosphorylation and ubiquitination, control NLRP3 protein degradation and inflammasome activation; however, the function of small ubiquitin-like modifier (SUMO) modification (called SUMOylation) in controlling NLRP3 stability and subsequent inflammasome activation is unclear. Here, we show that the E3 SUMO ligase tripartite motif-containing protein 28 (TRIM28) is an enhancer of NLRP3 inflammasome activation by facilitating NLRP3 expression. TRIM28 binds NLRP3, promotes SUMO1, SUMO2 and SUMO3 modification of NLRP3, and thereby inhibits NLRP3 ubiquitination and proteasomal degradation. Concordantly, Trim28 deficiency attenuates NLRP3 inflammasome activation both in vitro and in vivo. These data identify a mechanism by which SUMOylation controls the cellular NLRP3 level and inflammasome activation, and reveal correlations and interactions of NLRP3 SUMOylation and ubiquitination during inflammasome activation.

scholarly journals NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis

2018 ◽  
Vol 194 (2) ◽  
pp. 231-243 ◽  
Author(s):  
C. Guo ◽  
R. Fu ◽  
S. Wang ◽  
Y. Huang ◽  
X. Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hui Song ◽  
Chunyuan Zhao ◽  
Zhongxia Yu ◽  
Qizhao Li ◽  
Rongzhen Yan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Danger Signals ◽  
Nlrp3 Inflammasome Activation ◽  
Microbial Infections ◽  
Nlrp3 Expression

AbstractNOD-like receptor protein 3 (NLRP3) detects microbial infections or endogenous danger signals and activates the NLRP3 inflammasome, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases, and thereby needs to be tightly controlled. Deubiquitination of NLRP3 is considered a key step in NLRP3 inflammasome activation. However, the mechanisms by which deubiquitination controls NLRP3 inflammasome activation are unclear. Here, we show that the UAF1/USP1 deubiquitinase complex selectively removes K48-linked polyubiquitination of NLRP3 and suppresses its ubiquitination-mediated degradation, enhancing cellular NLRP3 levels, which are indispensable for subsequent NLRP3 inflammasome assembly and activation. In addition, the UAF1/USP12 and UAF1/USP46 complexes promote NF-κB activation, enhance the transcription of NLRP3 and proinflammatory cytokines (including pro-IL-1β, TNF, and IL-6) by inhibiting ubiquitination-mediated degradation of p65. Consequently, Uaf1 deficiency attenuates NLRP3 inflammasome activation and IL-1β secretion both in vitro and in vivo. Our study reveals that the UAF1 deubiquitinase complexes enhance NLRP3 and pro-IL-1β expression by targeting NLRP3 and p65 and licensing NLRP3 inflammasome activation.

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