Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis

Yin, Yuye; Yang, Xinyi; Wu, Shusheng; Ding, Xinyu; Zhu, Huamin; Long, Xuehui; Wang, Yuliang; Zhai, Sulan; Chen, Yun; Che, Nan; Chen, Jingjing; Wang, Xiaoming

doi:10.1038/s41590-022-01287-y

Cited by 28 publications

(12 citation statements)

References 63 publications

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“…In 1 study, STAT3 knockout or demethylation in RA mice reduced the differentiation frequency of immune cells and osteoclast activity, which hindered joint erosion. [33,34] High levels of TNF-α and IL-1β, 2 common inflammatory cytokines, were detected in the synovial fluid of RA patients. [35] Melittin was recently reported to inhibit IL-1β and TNF-α levels ,and therefore, the activation of JNK (c-Jun N-terminal kinase) and P38MAPK decreased.…”

Section: Discussionmentioning

confidence: 99%

Exploring potential network pharmacology-and molecular docking-based mechanism of melittin in treating rheumatoid arthritis

Wei

Gong

et al. 2023

Medicine

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Background: Rheumatoid arthritis (RA) is a type of difficult-to-cure arthralgia with a worldwide prevalence. It severely affects people’s living standards. For a long time, bee venom has been used to treat RA and has shown good results. Melittin is the main active component of bee venom used for RA treatment, but the molecular mechanism of melittin in RA treatments remains unclear. Methods: Potential melittin and RA targets were obtained from relevant databases, and common targets of melittin and RA were screened. The STRING database was used to build the PPI network and screen the core targets after visualization. The core targets were enriched by Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway. Finally, the binding of melittin to target proteins was evaluated through simulated molecular docking, which verified the reliability of the prediction results of network pharmacology. Results: In total, 138 melittin targets and 5795 RA targets were obtained from relevant databases, and 90 common targets were obtained through intersection. Eighteen core targets, such as STAT3, AKT1, tumor necrosis factor, and JUN, were screened out. Enrichment analysis results suggested that melittin plays an anti-RA role mainly through tumor necrosis factor, interleukin-17, toll-like receptors, and advanced glycation end products–RAGE signaling pathways, and pathogenic bacterial infection. Molecular docking results suggested that melittin has good docking activity with core target proteins. Conclusion: RA treatment with melittin is the result of a multi-target and multi-pathway interaction. This study offers a theoretical basis and scientific evidence for further exploring melittin in RA therapy.

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Section: Discussionmentioning

confidence: 99%

Exploring potential network pharmacology-and molecular docking-based mechanism of melittin in treating rheumatoid arthritis

Wei

Gong

et al. 2023

Medicine

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“…BAFF is crucial for B cells survival and development [20][21][22][23], however, in our study we only focused on BAFF expression in PMN-MDSCs, while other immune cells or FLS expression were not detected, whether PMN-MDSCs were the main source of BAFF in the joints and spleen was not known yet. Apart from TNF-α, B cells produced a variety of cytokines, such as IL-10, IL-6, GM-CSF and so on, which play important role in the pathogenesis of RA [34,35], and B cell also had subtypes, such as plasma B cell [36], marginal zone B cell [37], germinal centre B cell [38] and so on, however, in this work we did not explore the regulation of PMN-MDSCs to B cells differentiation and other cytokines production. Further studies were needed to understand how PMN-MDSCs regulates B cells.…”

Section: Discussionmentioning

confidence: 99%

Polymorphonuclear myeloid‐derived suppressor cells play a proinflammatory role via TNF‐α⁺ B cells through BAFF/BTK/NF‐κB signalling pathway in the pathogenesis of collagen‐induced arthritis mice

Tang

Shu

et al. 2023

Immunology

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Although various studies have been performed on the function of polymorphonuclear myeloid‐derived suppressor cells (PMN‐MDSCs) in RA, the results were conflicting. Here we were trying to clarify the role of PMN‐MDSCs in the pathogenesis of RA and its specific mechanisms. We detected the frequencies and counts of PMN‐MDSCs, TNF‐α+ B cells and Ki67+ B cells in spleen and inflamed joints of collagen‐induced arthritis (CIA) mice using flow cytometry. The pathological role of PMN‐MDSCs was examined by anti‐Ly6G neutralizing antibodies against PMN‐MDSCs or adoptive transfer of PMN‐MDSCs. And the modulation of PMN‐MDSCs on B cells was conducted by coculture assays, RNA‐Seq, RT‐qPCR, and so on. The mechanism of BAFF regulating B cells was verified through western blot and flow cytometry. PMN‐MDSCs accumulated in the spleen and joints of CIA mice. PMN‐MDSCs depletion could alleviate the arthritis severity, which was accompanied by decreased TNF‐α secretion and proliferation of B cells. And its adoptive transfer also facilitated disease progress. Furthermore, PMN‐MDSCs from CIA mice had higher expression level of BAFF, which regulated TNF‐α expression, proliferation and apoptosis of B cells in vitro. What's more, BAFF promoted phosphorylation of BTK/NF‐κB signalling pathway. And Ibrutinib (BTK inhibitor) could reverse the effect of BAFF on TNF‐α expression of B cells. Our study suggested that PMN‐MDSCs enhanced disease severity of CIA and manipulated TNF‐α expression, proliferation and apoptosis of B cells via BAFF, furthermore, BAFF promoted TNF‐α expression through BTK/NF‐κB signalling pathway, which demonstrated a novel pathogenesis of PMN‐MDSCs in CIA.

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“…A variety of important transcription factors participate in the pathogenesis of RA. Yin et al 103 reported that Jumonji domain containing 1C (JMJD1C), which were negatively associated with plasma cell frequency and disease severity in RA, demethylated STAT3 to restrain plasma cell differentiation and pathogenic immunoglobulin production. Yan et al 104 identified E26 transformation specific-1 (ETS1) drove the pathological tissue-remodeling programs in disease-associated FLS by orchestrating a previously undescribed regulatory elements (168 kb upstream of the TNFSF11 transcription start site) of the osteoclast differentiation factor RANKL.…”

Section: Transcription Factormentioning

confidence: 99%

Rheumatoid arthritis: pathogenesis and therapeutic advances

Gao,

Zhang,

Liu

2024

MedComm

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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the unresolved synovial inflammation for tissues‐destructive consequence, which remains one of significant causes of disability and labor loss, affecting about 0.2–1% global population. Although treatments with disease‐modifying antirheumatic drugs (DMARDs) are effective to control inflammation and decrease bone destruction, the overall remission rates of RA still stay at a low level. Therefore, uncovering the pathogenesis of RA and expediting clinical transformation are imminently in need. Here, we summarize the immunological basis, inflammatory pathways, genetic and epigenetic alterations, and metabolic disorders in RA, with highlights on the abnormality of immune cells atlas, epigenetics, and immunometabolism. Besides an overview of first‐line medications including conventional DMARDs, biologics, and small molecule agents, we discuss in depth promising targeted therapies under clinical or preclinical trials, especially epigenetic and metabolic regulators. Additionally, prospects on precision medicine based on synovial biopsy or RNA‐sequencing and cell therapies of mesenchymal stem cells or chimeric antigen receptor T‐cell are also looked forward. The advancements of pathogenesis and innovations of therapies in RA accelerates the progress of RA treatments.

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Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis

Cited by 28 publications

References 63 publications

Exploring potential network pharmacology-and molecular docking-based mechanism of melittin in treating rheumatoid arthritis

Exploring potential network pharmacology-and molecular docking-based mechanism of melittin in treating rheumatoid arthritis

Polymorphonuclear myeloid‐derived suppressor cells play a proinflammatory role via TNF‐α⁺ B cells through BAFF/BTK/NF‐κB signalling pathway in the pathogenesis of collagen‐induced arthritis mice

Rheumatoid arthritis: pathogenesis and therapeutic advances

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Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis

Cited by 28 publications

References 63 publications

Exploring potential network pharmacology-and molecular docking-based mechanism of melittin in treating rheumatoid arthritis

Exploring potential network pharmacology-and molecular docking-based mechanism of melittin in treating rheumatoid arthritis

Polymorphonuclear myeloid‐derived suppressor cells play a proinflammatory role via TNF‐α+ B cells through BAFF/BTK/NF‐κB signalling pathway in the pathogenesis of collagen‐induced arthritis mice

Rheumatoid arthritis: pathogenesis and therapeutic advances

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Polymorphonuclear myeloid‐derived suppressor cells play a proinflammatory role via TNF‐α⁺ B cells through BAFF/BTK/NF‐κB signalling pathway in the pathogenesis of collagen‐induced arthritis mice