{
  "abstract": "Background\n\nRheumatoid arthritis (RA) involves multiple pro-inflammatory cytokines; fibroblast-like synoviocytes (FLS) are central effector cells that integrate these signals to produce pathogenic mediators. Tumor necrosis factor (TNF) is a major upstream driver of coordinated inflammatory mediator induction in FLS; however, the underlying mechanisms remain incompletely defined, particularly intracellular feed-forward amplification sustaining and enhancing TNF-driven transcriptional outputs. Complement factor H (FH; gene CFH), a Sushi domain-only complement regulator, is elevated in RA serum. FH is regarded as an extracellular inhibitor of complement activation; however, its potential intracellular expression and functions in FLS have not been explored. We aimed to investigate intracellular FH expression and function using an in vitro transcribed messenger RNA (IVT mRNA)-based approach.Methods\n\nFH expression in sera, synovial tissues, and fibroblast-like synoviocytes (FLS) were assessed by enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, RT-qPCR, and immunoblotting. To examine intracellular FH function, FLS were transfected with CFH-encoding IVT mRNA to express FH intracellularly, followed by next-generation sequencing (RNA-seq), RT-qPCR, ELISA, phosphorylation assays, and pathway inhibition. Interactions between TNF-driven signaling and intracellular FH were evaluated using TNF- and/or FH-neutralizing antibodies, with or without CFH-targeting small interfering RNA (siRNA).Results\n\nFH was highly expressed in RA synovium and predominantly localized intracellularly in FLS. To assess intracellular FH function, FLS were transfected with CFH-encoding IVT mRNA, which induced the coordinated upregulation of RA-relevant mediators, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-8, IL-6, and multiple chemokines. Mechanistically, intracellular FH activated nuclear factor-κB (NF-κB) signaling, promoting receptor-interacting serine/threonine-protein kinase 2 (RIPK2) phosphorylation and p65 nuclear translocation, and the competitive nucleotide-binding oligomerization domain 2 (NOD2) antagonist suppressed FH-driven gene induction. TNF and intracellular FH additively enhanced pathogenic mediator production. CFH-targeting siRNA attenuated TNF-induced cytokine and chemokine expression; blockade of extracellular FH had no detectable effect. Combined TNF neutralization and CFH knockdown produced more effective suppression of cytokine induction than either intervention alone.Conclusions\n\nIntracellular FH is a previously unrecognized amplifier of TNF-driven inflammation in RA-FLS via a NOD2/RIPK2/NF-κB axis, establishing a feed-forward loop boosting pathogenic mediator production. Dual targeting of TNF and intracellular FH may represent a therapeutic strategy to suppress synovial inflammation more effectively.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan.",
    "Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan. sho-mokuda@hiroshima-u.ac.jp.",
    "Division of Laboratory Medicine, Hiroshima University Hospital, Hiroshima, 734-8551, Japan. sho-mokuda@hiroshima-u.ac.jp.",
    "Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Hiroki Kobayashi"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Sho Mokuda"
    },
    {
      "affs": [
        0
      ],
      "name": "Michinori Ishitoku"
    },
    {
      "affs": [
        0
      ],
      "name": "Hirofumi Watanabe"
    },
    {
      "affs": [
        0
      ],
      "name": "Tomohiro Sugimoto"
    },
    {
      "affs": [
        0
      ],
      "name": "Yusuke Yoshida"
    },
    {
      "affs": [
        3
      ],
      "name": "Junya Masumoto"
    },
    {
      "affs": [
        0
      ],
      "name": "Shintaro Hirata"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2ct0r6px3mfsw.bib",
  "cited_by": 0,
  "doi": "10.1186/s41232-026-00437-1",
  "fulltext_url": "https://europepmc.org/articles/PMC13721194",
  "id": "2ct0r6px3mfsw",
  "issns": [
    "1880-9693",
    "1880-8190"
  ],
  "landing_url": "https://europepmc.org/article/MED/42963795",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2745|Rheumatoid Arthritis Research and Therapies"
    ]
  ],
  "openalex": "W7172417947",
  "pdf_url": "https://europepmc.org/articles/PMC13721194?pdf=render",
  "pmcid": "PMC13721194",
  "pmid": "42963795",
  "published": "2026-08-04",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/2ct0r6px3mfsw.ris",
  "sources": [
    {
      "first_seen": "2026-11-02T03:21:43Z",
      "native_id": "MED:42963795",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42963795"
    },
    {
      "first_seen": "2026-11-03T12:21:55Z",
      "native_id": "PMC13721194",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s41232-026-00437-1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2745|Rheumatoid Arthritis Research and Therapies",
      "subfield": "general"
    }
  ],
  "title": "TNF-driven intracellular complement factor H-NF-κB feed-forward loop amplifies inflammatory mediator production in rheumatoid arthritis synovial fibroblasts.",
  "title_text": "TNF-driven intracellular complement factor H-NF-κB feed-forward loop amplifies inflammatory mediator production in rheumatoid arthritis synovial fibroblasts.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:21:55Z",
  "url": "https://research.draconitic.com/paper/2ct0r6px3mfsw",
  "venue": "Inflammation and regeneration",
  "versions": []
}