<scp>NLRP</scp>3 p.Q705K and <scp>CARD</scp>8 p.C10X single nucleotide polymorphisms are not associated with susceptibility to rheumatoid arthritis: a meta‐analysis

Yang, Zepeng; Cao, Jiangwei; Yang, Qingrui; Zhang, Yuanchao; Han, Lihui

doi:10.1111/1756-185x.13016

Cited by 15 publications

(9 citation statements)

References 44 publications

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“…In A20myel‐knock‐out (KO) mice, synovial inflammation and cartilage destruction were protected markedly by NLRP3, caspase‐1 or IL‐1 deletion . In humans, the NLRP3 gene polymorphism was reported to be associated with susceptibility, disease activity or anti‐TNF treatment response in RA . NLRP3 mRNA levels were also found to be up‐regulated in the synovia of RA patients compared to OA patients .…”

Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis

Guo

Wang

et al. 2018

Clinical and Experimental Immunology

219

180

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Summary Nucleotide‐binding, oligomerization domain (NOD)‐like receptor family, pyrin domain containing 3 (NLRP3) gene polymorphism was reported to be associated with susceptibility, disease activity or anti‐tumour necrosis factor (TNF) treatment response in rheumatoid arthritis (RA). However, the roles of NLRP3 inflammasome in the development of RA have not yet been elucidated fully. The present study aimed to study the role of NLRP3 inflammasome in RA. NLRP3 inflammasome activation in synovial tissues from RA and osteoarthritis (OA) patients were assessed by Western blot. Active caspase‐1 in synovia was stained by a FAM‐FLICA caspase‐1 probe. Mice with collagen‐induced arthritis (CIA) were treated with MCC950, a selective NLRP3 inhibitor, or vehicle for 2 weeks. The clinical score of arthritis, synovial inflammation and cartilage erosion were assessed. Proinflammatory cytokines were measured by enzyme‐linked immunosorbent assay (ELISA). The results showed that NLRP3 inflammasome was highly activated in both synovia from RA patients and CIA mice. Activation of NLRP3 inflammasome occurred mainly in the infiltrating monocyte/macrophages in synovia, but not in fibroblast‐like synoviocytes. Treatment with MCC950 resulted in significantly less severe joints inflammation and bone destruction. NLRP3 inflammasome activation in the synovia was inhibited significantly by MCC950 with reduced production of interleukin (IL)‐1β. The inhibition of NLRP3 inflammasome activation by MCC950 was confirmed further in a human monocytic cell line, THP‐1. In conclusion, NLRP3 inflammasome is involved in the pathogenesis of RA. Targeting NLRP3 inflammasome with a small molecule inhibitor might be a novel therapeutic strategy for RA.

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Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis

Guo

Wang

et al. 2018

Clinical and Experimental Immunology

219

180

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“…NLRP3 binds with the adaptor apoptosis-associated speck-like protein (ASC) and triggers the cleavage/activation of pro-caspase-1, which catalyzes the activation of IL-1β, contributing to the progression of inflammation [96]. Genetic variants within the NLRP3-inflammasome are associated with susceptibility to RA [97][98][99][100][101], and enhanced activity of NLRP3 inflammasome has been found in peripheral blood cells of patients with active RA [102]. Inhibition of NLRP3 inflammasome activity alleviated arthritis in CIA mice [103].…”

Section: Discussionmentioning

confidence: 99%

High susceptibility to collagen-induced arthritis in mice with progesterone receptors selectively inhibited in osteoprogenitor cells

Liu¹,

Jia²,

Jiang

et al. 2020

Preprint

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Abstract Background. Progesterone receptor (PR) affects immunomodulation, and lack of PR in osteoprogenitor cells primarily affects pathways associated with immunomodulation, especially in the males. In this study, we selectively deleted PR from osteoprogenitor cells using Prx1-Cre to evaluate the tissue-specific effects of PR on inflammatory arthritis (IA). Methods. Collagen-induced arthritis (CIA) was used as an IA animal model, which we induced in PR D Prx1 mice and their wild type (WT) littermates were immunized with collagen II (CII) emulsified incomplete Freund's adjuvant ( CFA ) in both sexes. Joint erosion, inflammation, and cartilage damages were assessed using a semiquantitative histologic scoring system. Bone volume and erosions in knee and ankle joints were quantitated using microCT. We found that knee and paw joint erosions developed in 37.5% and 41.7% of the WT and PR D Prx1 female mice, respectively, and in 45.4 and 100%, respectively, of the male mice. Also, both knee and ankle joint inflammation scores, joint damage scores, and subchondral bone erosions were significantly more severe in male PRcKO mice than in male WT mice. Although of lower severity than in male mice, female PR D Prx1 mice also developed higher inflammation scores and bone erosions than the KO-normal or WT-CIA females. Immunohistochemistry staining of the NLRP3 inflammasome revealed the male PR D Prx1 mice had significantly higher expression of NLRP3 inflammasome in the knee joints. Conclusion. Our observations indicate that the presence of PR in osteoprogenitor cells counteracts the development of collagen-induced arthritis and might help to explain the sex differences observed in human inflammatory arthritis.

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“…The nonsynonymous gain‐of‐function polymorphism NLRP3 rs35829419 (p. Q705K) leads to an overactive NLRP3 inflammasome, while caspase recruitment domain‐containing protein 8 (CARD8) rs2043211 (p. C10X) polymorphism encodes a truncated protein that does not inhibit the nuclear factor‐κB (NF‐κB) stimulation of inflammatory response . It was suggested that interaction between NLRP3 rs35829419 and CARD8 rs2043211 increases susceptibility to several inflammatory diseases and bacteriemia, but the results are inconclusive and have not been tested on patients with hip arthroplasty implants so far.…”

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confidence: 89%

Association of NLRP3 and CARD8 Inflammasome Polymorphisms With Aseptic Loosening After Primary Total Hip Arthroplasty

Mavčič

Antolič

Dolžan

2019

Journal Orthopaedic Research

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Our aim was to investigate the association of inflammasome polymorphisms NLRP3 rs35829419 (p. Q705K) and CARD8 rs2043211 (p. C10X) with aseptic loosening of total hip endoprostheses. We asked whether patients with the loosening of total hip arthroplasty earlier than 15 years after primary implantation had a higher proportion of the polymorphisms Q705K and C10X in comparison to subjects without loosening. A retrospective case-control study compared 36 patients with total hip endoprosthesis loosening earlier than 15 years after primary implantation and 51 control subjects with unloosened total hip endoprostheses, matched for gender, age, and follow-up period. Buccal mucosa samples were used for genomic DNA analysis and genotyped for NLRP3 rs35829419 and CARD8 rs2043211 using a fluorescence-based competitive allele-specific real-time polymerase chain reaction. The proportion of subjects with both wild-type NLRP3 and CARD8 (i.e., without Q705K or C10X) was considerably higher in the control group when compared with patients with early total hip arthroplasty loosening (49% vs. 28%; p = 0.05). After adjustment for gender, age, and followup, patients with combined wild type of both NLRP3 and CARD8 had significantly smaller odds for early implant loosening (odds ratio 0.33, p = 0.02). Investigated polymorphisms may influence several inflammatory pathways and contribute to the loosening of artificial implants with potential clinical significance for the appropriate selection of patients and endoprostheses when planning elective total hip arthroplasty.

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NLRP3 p.Q705K and CARD8 p.C10X single nucleotide polymorphisms are not associated with susceptibility to rheumatoid arthritis: a meta‐analysis

Abstract: NLRP3 p.Q705K and CARD8 p.C10X polymorphisms were not associated with the susceptibility to RA, separately or in combined forms.

Cited by 15 publications

References 44 publications

NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis

NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis

High susceptibility to collagen-induced arthritis in mice with progesterone receptors selectively inhibited in osteoprogenitor cells

Association of NLRP3 and CARD8 Inflammasome Polymorphisms With Aseptic Loosening After Primary Total Hip Arthroplasty

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