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Systemic sclerosis
Human hypofunctional NCF1 variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1+ monocytes-derived macrophages
  1. Xinran Yuan1,2,
  2. Xiaodong Qin3,
  3. Kenji Takemoto1,
  4. Jian Zhao1,
  5. Matthew Sanderson1,
  6. Xue Xu1,
  7. Yu Zhang1,
  8. Kristi L Helke4,
  9. Bethany Jacobs Wolf5,
  10. Joel M Guthridge6,
  11. Judith A James6,
  12. Xiaodong Zhou7,
  13. Shervin Assassi7,
  14. Carol Feghali-Bostwick1,
  15. Dandan Wang2,
  16. Lingyun Sun2,
  17. Betty P Tsao1
  1. 1Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
  2. 2Department of Rheumatology and Immunology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
  3. 3Department of Orthopedic Surgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
  4. 4Department of Comparative Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
  5. 5Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
  6. 6Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  7. 7Division of Rheumatology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
  1. Correspondence to Dr Betty P Tsao; tsaob{at}musc.edu; Professor Lingyun Sun; lingyunsun{at}nju.edu.cn

Abstract

Objective We assessed the role of a systemic lupus erythematosus causal hypofunctional variant, neutrophil cytosolic factor 1 (NCF1)-p.Arg90His (p.R90H) substitution, in systemic sclerosis (SSc).

Methods Association of NCF1-H90 with SSc was performed in case–control cohorts, bleomycin (BLM)-treated Ncf1-R90 C57BL/6 wildtype and Ncf1-H90 knock-in (KI) littermates. Peripheral blood mononuclear cell (PBMC) subsets were analysed by cytometry by time-of-flight.

Results The NCF1-H90 allele is associated with risk for diffuse cutaneous SSc (dcSSc) in Chinese and European Americans, and lung fibrosis in Chinese patients with SSc (OR=2.09, p=7.96E−10). Low copy number of NCF1 associated with lung fibrosis in European Americans (OR=4.33, p=2.60E−2). BLM-treated KI mice demonstrated increased pulmonary fibrosis, exhibiting activated type I interferon signature, elevated Spp1, Ccl2, Arg1, Timp1 and Il6 expression, enriched macrophage scores in lung tissues. In a longitudinal observation cohort, homozygous H90 patients with SSc at baseline had increased anti-nuclear antibody titres, anti-topoisomerase antibody seropositivity and anti-centromere antibody seronegativity, increased incidence of lung fibrosis and Gender-Age-lung Physiology index, elevated modified Rodnan Skin Score (mRSS) and elevated plasma osteopontin (OPN, SPP1), CCL2, ARG1, TIMP-1 and IL-6. These H90 patients with SSc sustained elevated mRSS during follow-up years with decreased survival. The 0, 1 and 2 copies of H90 carriage in SSc PBMCs exhibited dose-dependent increases in profibrotic CD14+CD68+CD11b+Tim3+monocytes. Elevated OPN, CCL2 and ARG1 in CD68+CD11b+monocyte-derived macrophages from H90 patients were decreased after co-culturing with anti-CCL2 antibody.

Conclusion Low NCF1 activity increases the risk for the development of dcSSc and lung fibrosis via expanding profibrotic SPP1+MoMs in a CCL2-dependent manner, contributing to the severity of lung fibrosis in both BLM-treated mice and patients with SSc.

  • Scleroderma, Systemic
  • Pulmonary Fibrosis
  • Polymorphism, Genetic

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/ard-2024-226034

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • Handling editor Josef S Smolen

    • X @ShervinAssassi

    • XY, XQ and KT contributed equally.

    • Correction notice This article has been corrected since it published Online First. A corresponding author has been added.

    • Contributors BPT, LS and CF-B designed the study. SA, XZ and XX provided the DNA samples of patients with systemic sclerosis (SSc). XY, KT, YZ and MS conducted the animal experiments. KLH provided histology assessment of mouse lung tissues. JZ performed genotyping and association studies. XY and XQ performed the longitudinal study of patients with SSc. XY, XQ and DW performed the cytometry by time-of-flight and in vitro experiments for patients with SSc. XY, XQ and BJW analysed data and performed statistical analyses. BPT, XY and XQ drafted the manuscript. All authors edited and reviewed the manuscript. BPT is responsible for the overall content as guarantor.

    • Funding This work was supported by the National Scleroderma Foundation (grant to BPT), NIH R21 AR081933-01A1 (grant to BPT), MUSC COMETS-PPG (grant to BPT) and NIH/NIAMS R01 AR081280 (grant to SA).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.