Human Hypofunctional NCF1 Variants Promote Pulmonary Fibrosis in the Bleomycin-Induced Mouse Model and Patients With Systemic Sclerosis via Expansion of SPPHuman Hypofunctional NCF1 Variants Promote Pulmonary Fibrosis in the Bleomycin-Induced Mouse Model and Systemic Sclerosis Patients via Expansion of SPP1+ Monocytes-Derived Macrophages

Authors

Xinran Yuan
Xiaodong Qin
Kenji Takemoto
Jian Zhao
Matthew Sanderson
Xue Xu
Yu Zhang
Kristi L Helke
Bethany Jacobs Wolf
Joel M Guthridge
Judith A James
Xiaodong Zhou
Shervin Assassi
Carol Feghali-Bostwick
Dandan Wang
Lingyun Sun
Betty P Tsao

Publication Date

2-1-2025

Journal

Annals of the Rheumatic Diseases

DOI

10.1136/ard-2024-226034

PMID

39919902

PMCID

PMC11907366

PubMedCentral® Posted Date

2-1-2026

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Animals, Bleomycin, Humans, Pulmonary Fibrosis, Mice, Scleroderma, Systemic, Disease Models, Animal, Macrophages, Female, Male, Mice, Inbred C57BL, Osteopontin, NADPH Oxidases, Case-Control Studies, Middle Aged, Adult, Monocytes, Genetic, Polymorphism, Pulmonary Fibrosis, Scleroderma, Systemic

Published Open-Access

yes

Recommended Citation

Yuan, Xinran; Qin, Xiaodong; Takemoto, Kenji; et al., "Human Hypofunctional NCF1 Variants Promote Pulmonary Fibrosis in the Bleomycin-Induced Mouse Model and Patients With Systemic Sclerosis via Expansion of SPPHuman Hypofunctional NCF1 Variants Promote Pulmonary Fibrosis in the Bleomycin-Induced Mouse Model and Systemic Sclerosis Patients via Expansion of SPP1+ Monocytes-Derived Macrophages" (2025). Faculty, Staff and Student Publications. 5312.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5312