{
  "abstract": "Introduction: Rheumatoid arthritis–associated interstitial lung disease (RA-ILD) is a major extra-articular complication of rheumatoid arthritis and a leading cause of morbidity and mortality. Unlike idiopathic pulmonary fibrosis (IPF), RA-ILD develops in the context of systemic immune activation, but the cellular basis linking inflammation to fibroblast-state changes remains incompletely understood.\n\nMethods: We performed single-cell RNA sequencing on lung tissues from healthy donors, patients with RA-ILD, and patients with IPF, complemented by spatial validation and in vitro experiments.\n\nResults: In this cohort, RA-ILD lungs showed an increased proportion of FCN1⁺ inflammatory macrophages within the macrophage compartment, whereas IPF lungs were dominated by SPP1⁺ macrophages. Trajectory and cell–cell communication analyses identified an RA-ILD-enriched matrix-fibroblast-to-CXCR4⁺ lipofibroblast program and a predicted SEMA3C–NRP1 interaction between inflammatory macrophage populations and fibroblasts; these patterns were not detected in the IPF or healthy-control samples analyzed here. Multiplex immunofluorescence showed macrophage-associated SEMA3C signal in spatial proximity to NRP1⁺ fibroblasts within fibrotic regions. A flow-sorted inflammatory monocyte/macrophage-enriched population from RA-ILD lungs had higher supernatant SEMA3C levels and was associated with shifts in MRC-5 fibroblast markers from EBF1/PDGFRA toward APOE/CXCR4. Recombinant SEMA3C reproduced this marker-defined shift, whereas pharmacological NRP1 inhibition attenuated it; an orthogonal THP-1 overexpression model produced concordant results.\n\nDiscussion: These data support an association between an inflammatory macrophage–SEMA3C–NRP1 axis and fibroblast-state remodeling in the studied RA-ILD samples. Because the RA-ILD cohort was small and did not include other CTD-ILD subtypes, the findings should not be interpreted as establishing RA-ILD specificity or a fully profibrotic functional phenotype.",
  "abstract_shown": true,
  "affiliations": [
    "Senior Department of Respiratory and Critical Care Medicine, the Eighth Medical Center of PLA General Hospital",
    "Medical School of Chinese PLA",
    "Respiratory Research Institute, Department of Pulmonary & Critical Care Medicine, the Eighth Medical Center of PLA General Hospital",
    "Beijing Key Laboratory of OTIR"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Ruofan Su"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Licheng Song"
    },
    {
      "affs": [
        0
      ],
      "name": "Xuxin Chen"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yaru Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yi Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Chunyang Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Junjie Du"
    },
    {
      "affs": [
        0
      ],
      "name": "Dingyun Song"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Li Xiao"
    },
    {
      "affs": [
        0
      ],
      "name": "Lixin Xie"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhihai Han"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ec5xbebzvv24x.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1978823",
  "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978823/full",
  "id": "ec5xbebzvv24x",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978823/full",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "RC581-607"
    ],
    [
      "openalex",
      "2740|Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis"
    ]
  ],
  "openalex": "W7223259261",
  "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1978823/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-23",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/ec5xbebzvv24x.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:17Z",
      "native_id": "10.3389/fimmu.2026.1978823",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978823/full"
    },
    {
      "first_seen": "2026-10-30T13:43:58Z",
      "native_id": "a33b0760b6b34e37b5f246b2e0fb5a08",
      "source": "doaj",
      "url": "https://doi.org/10.3389/fimmu.2026.1978823"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "issn:1664-3224",
      "subfield": "immunology"
    },
    {
      "field": "medicine",
      "origin": "lcc:RC581-607",
      "subfield": "general"
    }
  ],
  "title": "An FCN1+ macrophage-associated SEMA3C–NRP1 axis is linked to fibroblast reprogramming in RA-ILD",
  "title_text": "An FCN1+ macrophage-associated SEMA3C–NRP1 axis is linked to fibroblast reprogramming in RA-ILD",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:43:58Z",
  "url": "https://research.draconitic.com/paper/ec5xbebzvv24x",
  "venue": "Frontiers in Immunology",
  "versions": []
}