RT Journal Article
SR Electronic
T1 Human hypofunctional <em>NCF1</em> variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1<sup>+</sup> monocytes-derived macrophages
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP ard-2024-226034
DO 10.1136/ard-2024-226034
A1 Yuan, Xinran
A1 Qin, Xiaodong
A1 Takemoto, Kenji
A1 Zhao, Jian
A1 Sanderson, Matthew
A1 Xu, Xue
A1 Zhang, Yu
A1 Helke, Kristi L
A1 Jacobs Wolf, Bethany
A1 Guthridge, Joel M
A1 James, Judith A
A1 Zhou, Xiaodong
A1 Assassi, Shervin
A1 Feghali-Bostwick, Carol
A1 Wang, Dandan
A1 Sun, Lingyun
A1 Tsao, Betty P
YR 2024
UL http://ard.bmj.com/content/early/2024/09/23/ard-2024-226034.abstract
AB 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.All data relevant to the study are included in the article or uploaded as supplementary information.