TNF-α/calreticulin dual signaling induced NLRP3 inflammasome activation associated with HuR nucleocytoplasmic shuttling in rheumatoid arthritis

Liu, Yixin; Wei, Wei; Wang, Yan; Wan, Chunyou; Bai, Yingyu; Sun, Xin; Ma, Jun; Zheng, Fang

doi:10.1007/s00011-019-01244-w

Cited by 39 publications

(33 citation statements)

References 44 publications

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“…Furthermore, our study further clarified the mechanism by which Gent regulated abnormal proliferation, migration, and inflammatory processes of RA-FLS. NLRP3 inflammasome assembly results in caspase-1 activation and consequent IL-1b secretion (Gaidt et al, 2016;Liu et al, 2019). The NLRP3 has been found to serve as a key driver of several autoimmune conditions including both RA and systemic lupus erythematosus (SLE) (Shen et al, 2018).…”

mentioning

confidence: 99%

Anti-Rheumatic Properties of Gentiopicroside Are Associated With Suppression of ROS-NF-κB-NLRP3 Axis in Fibroblast-Like Synoviocytes and NF-κB Pathway in Adjuvant-Induced Arthritis

Wang

et al. 2020

Front. Pharmacol.

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Rheumatoid arthritis (RA) is among the most prevalent forms of autoimmunity. Gentiopicroside (Gent) is an iridoid glucoside derived from the Gentiana Macrophylla Pall which is used in traditional Chinese medicine to treat RA. The present study was designed to explore the ability of Gent to combat RA and to explore the molecular basis for such anti-RA activity both in vitro using tumor necrosis factor alpha (TNF-a)-stimulated human RA fibroblast-like synoviocytes (RA-FLS) and in vivo using a rat adjuvant-induced arthritis (AIA) model. We found that Gent was able to significantly reduce the swelling of joints and arthritic index scores, with corresponding reductions in synovial inflammatory cell infiltration, synovial hyperplasia, and bone erosion in treated AIA rats. Importantly, Gent 200 mg/kg reduced thymus index in AIA rats, but had no effect on spleen index and body weight, it revealed that Gent was relatively safe at the dose we chose. We further found that Gent was able to suppress the TNF-a-induced proliferation and migration of RA-FLS cells. This suppression was attributed to the ability of Gent to block NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1, thereby disrupting the activation of the NLRP3 inflammasome. Consistent with such suppression, Gent led to a significant decrease in IL-1b secretion by treated cells. Furthermore, this reduction in NLRP3 inflammasome activation was also associated with decreases in the activation of nuclear factor (NF-kB), the production of reactive oxygen species (ROS), and the expression of inflammatory IL-6. Together these findings indicate that Gent can suppress the ROS-NF-kB-NLRP3 axis to alleviate RA symptoms.

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confidence: 99%

Anti-Rheumatic Properties of Gentiopicroside Are Associated With Suppression of ROS-NF-κB-NLRP3 Axis in Fibroblast-Like Synoviocytes and NF-κB Pathway in Adjuvant-Induced Arthritis

Wang

et al. 2020

Front. Pharmacol.

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“…An increasing number of studies have shown RA symptoms may be improved following suppression of the NLRP3 pathway that might suggest the NLRP3 pathway serves an important role in the severity of RA ( 29 , 30 ). It has also been proposed that NLRP3 may be a promising therapeutic target in autoimmune diseases, including RA ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a positive correlation between NLRP3 mRNA expression and DAS28/CRP/ESR was also observed in patients with RA, suggesting that the NLRP3 inflammasome maybe closely associated with RA activity. It was suggested that DAS28, CRP and ESR in patients with RA could be decreased by inhibiting the NLRP3 pathway, which was mainly based on the results of previously published articles that demonstrated that RA symptoms might be improved following inhibition of the NLRP3 pathway ( 29 , 30 ). However, further research would be required to confirm the association of the severity of RA and the NLRP3 pathway.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 gene polymorphisms and expression in rheumatoid arthritis

et al. 2021

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The present study aimed to investigate the association between the single-nucleotide polymorphisms (SNPs) rs4612666 and rs10754558 in the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) gene and the susceptibility to rheumatoid arthritis (RA) in a Han Chinese population. mRNA expression of NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1 were determined in peripheral blood mononuclear cells (PBMCs) and neutrophils using reverse-transcription quantitative PCR. The results demonstrated that the C allele at rs4612666 locus and the G allele at rs10754558 locus were associated with significantly increased risk of RA. A statistical significance was also revealed in the dominant model (CC+CT vs. TT: OR=1.549; 95% CI=1.120-2.144; and GG + GC vs. CC: OR=2.000; 95% CI=1.529-2.616; P<0.05). Additionally, the mRNA expression of NLRP3, ASC and caspase-1 in PBMCs and neutrophils derived from patients with RA were significantly upregulated compared with the controls. Furthermore, the mRNA levels of NLRP3, ASC and caspase-1 in PBMCs and neutrophils from patients with active RA were notably increased compared with patients in remission. NLRP3 expression was positively correlated with the levels of C-reaction protein, erythrocyte sedimentation rate and disease activity score of 28 joint counts. Overall, the current study indicated that the NLRP3 rs4612666 and rs10754558 loci were associated with susceptibility to RA. In addition, the results of the present study demonstrated that the high expression of NLRP3 could serve a critical role in the pathogenesis of RA.

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“…However, FLS require an additional signal to induce inflammasome activation but this can be achieved by extracellular calreticulin which is elevated in RA joint and serum where it correlates with disease activity leading to an increase in IL-1β release. [117][118][119] In addition, IL-6 can enhance monocyte NLRP3 overactivation and pyroptosis, induced by pentraxin-3 (PTX3) and C1q which are elevated in RA serum. 120 Furthermore, inhibition of IL-6 in the CIA model reduces NLRP3 activation and IL-1β release.…”

Section: Dovepressmentioning

confidence: 99%

Contribution of Toll-Like Receptors and the NLRP3 Inflammasome in Rheumatoid Arthritis Pathophysiology

Unterberger¹,

Davies²,

Rambhatla³

et al. 2021

ITT

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Rheumatoid arthritis (RA) is a progressive autoimmune disease that is characterized by inflammation of the synovial joints leading to cartilage and bone damage. The pathogenesis is sustained by the production of pro-inflammatory cytokines including tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6, which can be targeted therapeutically to alleviate disease severity. Several innate immune receptors are suggested to contribute to the chronic inflammation in RA, through the production of pro-inflammatory factors in response to endogenous danger signals. Much research has focused on toll-like receptors and more recently the nucleotide-binding domain and leucine-rich repeat pyrin containing protein-3 (NLRP3) inflammasome, which is required for the processing and release of IL-1β. This review summarizes the current understanding of the potential involvement of these receptors in the initiation and maintenance of inflammation and tissue damage in RA and experimental arthritis models.

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TNF-α/calreticulin dual signaling induced NLRP3 inflammasome activation associated with HuR nucleocytoplasmic shuttling in rheumatoid arthritis

Cited by 39 publications

References 44 publications

Anti-Rheumatic Properties of Gentiopicroside Are Associated With Suppression of ROS-NF-κB-NLRP3 Axis in Fibroblast-Like Synoviocytes and NF-κB Pathway in Adjuvant-Induced Arthritis

Anti-Rheumatic Properties of Gentiopicroside Are Associated With Suppression of ROS-NF-κB-NLRP3 Axis in Fibroblast-Like Synoviocytes and NF-κB Pathway in Adjuvant-Induced Arthritis

NLRP3 gene polymorphisms and expression in rheumatoid arthritis

Contribution of Toll-Like Receptors and the NLRP3 Inflammasome in Rheumatoid Arthritis Pathophysiology

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