An FCN1+ macrophage-associated SEMA3C–NRP1 axis is linked to fibroblast reprogramming in RA-ILD
4 affiliations
- 1Senior Department of Respiratory and Critical Care Medicine, the Eighth Medical Center of PLA General Hospital
- 2Medical School of Chinese PLA
- 3Respiratory Research Institute, Department of Pulmonary & Critical Care Medicine, the Eighth Medical Center of PLA General Hospital
- 4Beijing Key Laboratory of OTIR
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.
Methods: 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.
Results: 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.
Discussion: 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.
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BibTeX
@article{su2026fcn1,
title = {{An FCN1+ macrophage-associated SEMA3C–NRP1 axis is linked to fibroblast reprogramming in RA-ILD}},
author = {Ruofan Su and Licheng Song and Xuxin Chen and Yaru Liu and Yi Yang and Chunyang Zhang and Junjie Du and Dingyun Song and Li Xiao and Lixin Xie and Zhihai Han},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1978823},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978823/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - An FCN1+ macrophage-associated SEMA3C–NRP1 axis is linked to fibroblast reprogramming in RA-ILD
AU - Ruofan Su
AU - Licheng Song
AU - Xuxin Chen
AU - Yaru Liu
AU - Yi Yang
AU - Chunyang Zhang
AU - Junjie Du
AU - Dingyun Song
AU - Li Xiao
AU - Lixin Xie
AU - Zhihai Han
PY - 2026
DA - 2026/10/23
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1978823
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978823/full
AB - 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. Methods: 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. Results: 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. Discussion: 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.
SN - 1664-3224
ER -