Gout-associated monosodium urate crystal-induced necrosis is independent of NLRP3 activity but can be suppressed by combined inhibitors for multiple signaling pathways

Zhong, Chun-Su; Zeng, Bo; Qiu, Jiahao; Xu, Lihui; Zhong, Mei-Yan; Huang, Yuanting; Xu, Rong; Liu, Siying; Zha, Qing-Bing; Hu, Bo; Ouyang, Dong-Yun; He, Xian-Hui

doi:10.1038/s41401-021-00749-7

Cited by 36 publications

(16 citation statements)

References 53 publications

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“…In CIA, crystals can affect apoptotic processes in various cells, including neutrophiles, through the release of ROS and NOS, thereby promoting apoptosis [ 17 ]. MSU and CPP crystals have also been shown to induce necrosis [ 18 ]. The percentage of karyorrhectic and karyolitic cells were higher in SF from RA patients with respect to the samples collected from the other groups and was positively associated with WBC count and the levels of IL-1β, IL-8, IL-10, TNF, and TGFβ.…”

Section: Discussionmentioning

confidence: 99%

Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies

Baggio

Luisetto

Boscaro

et al. 2023

IJMS

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Genome damage has been related to the induction of autoimmune processes, chronic inflammation, and apoptosis. Recent studies suggest that some rheumatological diseases are associated with overall genomic instability in the T cell compartment. However, no data regarding leucocyte abnormalities in synovial fluid (SF) and their relationship with inflammation are available. The aim of this study was to investigate cellular phenotypes in SF collected from patients with different inflammatory arthropathies, including rhematoid arthritis (RA), psoriatic arthritis (PsA), crystal-induced arthritis (CIA), and non-inflammatory arthropathies, such as osteoarthritis (OA). We found high percentage of micronuclei in SF from CIA compared to the other groups and a high frequency of pyknotic cell in RA and CIA patients. A correlation between pyknosis and immature polymorphonuclear cells with local inflammatory indices was observed. The study of the apoptosis process revealed an increased BAX expression in CIA and RA compared to OA and PsA, while Bcl-2 was higher in CIA. Caspase-3 activity was increased in SF from RA patients and correlates with inflammatory and anti-inflammatory cytokines. In conclusion, our results showed that inflammatory SF is associated with genomic instability and abnormal cell subsets.

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Section: Discussionmentioning

confidence: 99%

Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies

Baggio

Luisetto

Boscaro

et al. 2023

IJMS

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“…NLRP3 inflammasome inhibitor was also shown to suppress gouty arthritis in mice (Xue et al, 2021). However, another recent study showed that NLRP3 inhibitor did not significantly suppress MSU crystal-induced necrosis in macrophages (Zhong et al, 2021). This discrepancy indicates that more experiments need to be performed to clearly elucidate the role of NLRP3 in MSU crystal-induced gouty arthritis.…”

Section: Discussionmentioning

confidence: 99%

Active Flavonoids From Lagotis brachystachya Attenuate Monosodium Urate-Induced Gouty Arthritis via Inhibiting TLR4/MyD88/NF-κB Pathway and NLRP3 Expression

Ouyang

Guo

et al. 2021

Front. Pharmacol.

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Lagotis brachystachya Maxim is a characteristic herb commonly used in Tibetan medicine. Tibetan medicine records it as an important medicine for the clinical treatment of “Yellow Water Disease,” the symptoms of which are similar to that of arthritis. Our previous study showed that the flavonoid fraction extracted from L. brachystachya could attenuate hyperuricemia. However, the effects of the active flavonoids on gouty arthritis remain elusive, and the underlying mechanism is not understood. In the present study, the effects of the active flavonoids were evaluated in rats or Raw264.7 cells with gouty arthritis induced by monosodium urate (MSU) crystal, followed by the detection of TLR4, MyD88, pNF-κB, and NLR family pyrin domain-containing 3 (NLRP3) expression. The swelling of the ankle joint induced by MSU crystal began to be relieved 6 h post the administration with the active flavonoids. In addition, the active flavonoids not only alleviated MSU crystal-induced inflammation in synovial tissues by histopathological examination but also reduced tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in the joint tissue fluid of MSU crystal-induced rats. Furthermore, Western blot analysis indicated that the active flavonoids reduced the production of these cytokines by inhibiting the TLR4/MyD88/NF-κB pathway and decreasing NLRP3 expression in synovial tissues of rats. More importantly, the inhibition of TLR4/MyD88/NF-κB pathway and NLRP3 expression was also confirmed in MSU-induced Raw264.7 cells. In conclusion, these results indicated that the active flavonoids from L. brachystachya could effectively attenuate gouty arthritis induced by MSU crystal through the TLR4/MyD88/NF-κB pathway and NLRP3 expression in vivo and in vitro, suggesting several potential candidates for the treatment of gouty arthritis.

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“…However, the therapeutic potential of NSA in other retinal disorders is yet to be demonstrated. GW806742X is a potent MLKL inhibitor that binds the pseudokinase domain of MLKL 177 . Treatment with GW806742X and other RIPK1/3 inhibitors significantly blocked necroptosis and inflammation 178 , 179 .…”

Section: Therapeutic Options To Target Necroptosis In Retinamentioning

confidence: 99%

Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases

Zhang¹,

Hu²,

Zhao³

et al. 2023

Int. J. Biol. Sci.

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The discovery of the necroptosis, a form of regulated necrosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL), represents a major breakthrough that has dramatically altered the conception of necrosis -traditionally thought of as uncontrolled cell death -in various human diseases. Retinal cell death is a leading cause of blindness and has been identified in most retinal diseases, e.g., age-related macular degeneration, glaucoma, retinal detachment, retinitis pigmentosa, etc. Increasing evidence demonstrates that retinal degenerative diseases also share a common mechanism in necroptosis. Exacerbated necroptotic cell death hinders the treatment for retinal degenerative diseases. In this review, we highlight recent advances in identifying retinal necroptosis, summarize the underlying mechanisms of necroptosis in retinal degenerative diseases, and discuss potential anti-necroptosis strategies, such as selective inhibitors and chemical agents, for treating retinal degenerative diseases.

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Gout-associated monosodium urate crystal-induced necrosis is independent of NLRP3 activity but can be suppressed by combined inhibitors for multiple signaling pathways

Cited by 36 publications

References 53 publications

Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies

Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies

Active Flavonoids From Lagotis brachystachya Attenuate Monosodium Urate-Induced Gouty Arthritis via Inhibiting TLR4/MyD88/NF-κB Pathway and NLRP3 Expression

Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases

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