Neutrophil extracellular traps (NETs) are increased in rheumatoid arthritis-associated interstitial lung disease
Abstract Background Neutrophil extracellular trap (NET) formation has been implicated as a pathogenic mechanism in both rheumatoid arthritis (RA) and interstitial lung disease (ILD). However, the role of NETs in RA-associated ILD (RA-ILD) and the mechanisms driving NET formation remain unclear. This...
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BMC
2025-01-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-025-03111-1 |
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| author | Jing Xue Miaomiao Nian Yangyang Liang Zeqin Zhu Zhenyu Hu Yuanyuan Jia Shuhong Chi Juan Chen |
| author_facet | Jing Xue Miaomiao Nian Yangyang Liang Zeqin Zhu Zhenyu Hu Yuanyuan Jia Shuhong Chi Juan Chen |
| author_sort | Jing Xue |
| collection | DOAJ |
| description | Abstract Background Neutrophil extracellular trap (NET) formation has been implicated as a pathogenic mechanism in both rheumatoid arthritis (RA) and interstitial lung disease (ILD). However, the role of NETs in RA-associated ILD (RA-ILD) and the mechanisms driving NET formation remain unclear. This study aimed to assess the involvement of NETs in RA-ILD and elucidate the underlying mechanisms. Methods Single-cell sequencing was used to identify changes in the quantity and function of neutrophils in the lung tissue of a zymosan A (ZYM)-induced interstitial pneumonia arthritis model. Additionally, nuclear receptor 4A3 (NR4A3) interference was performed in HL-60 cells to assess its impact on NET formation and the transformation of MRC-5 cells into myofibroblasts. The clinical relevance of plasma myeloperoxidase-DNA (MPO-DNA), citrullinated histone 3 (Cit-H3), and cell-free DNA was evaluated in RA-ILD patients with different imaging types via a commercial enzyme-linked immunosorbent assay (ELISA). Results In the ZYM-treated SKG mouse model, which recapitulates key features of RA-ILD, an increased population of neutrophils in the lung tissue was primarily responsible for NET formation. Mechanistically, we found that interference with NR4A3 expression enhanced NET formation in HL-60 cells, which in turn promoted the differentiation of MRC-5 cells into myofibroblasts. Clinically, plasma MPO-DNA levels are elevated in patients with RA-nonspecific interstitial pneumonia (RA-NSIP), whereas Cit-H3 levels are elevated in RA-usual interstitial pneumonia (RA-UIP) patients compared with healthy subjects. ROC curve analysis further revealed that the combination of plasma MPO-DNA, rheumatoid factor (RF), and anti-citrullinated protein (anti-CCP) and the combination of Cit-H3, RF, and anti-CCP were superior diagnostic panels for NSIP and UIP in RA-ILD patients, respectively. Moreover, compared with those from healthy controls, neutrophils from patients with RA-UIP and RA-NSIP demonstrated a significantly increased ability to form NETs and induce the differentiation of MRC-5 cells into myofibroblasts. Specifically, RA-UIP patients exhibited a greater capacity for NET formation and the differentiation of MRC-5 cells into myofibroblasts than did RA-NSIP patients. Conclusions These findings suggest that targeting NETs may be a novel therapeutic approach for treating ILD in RA patients. |
| format | Article |
| id | doaj-art-5bf3549bd3b840faba215d9d3d0b90df |
| institution | Kabale University |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Respiratory Research |
| spelling | doaj-art-5bf3549bd3b840faba215d9d3d0b90df2025-01-26T12:48:55ZengBMCRespiratory Research1465-993X2025-01-0126111910.1186/s12931-025-03111-1Neutrophil extracellular traps (NETs) are increased in rheumatoid arthritis-associated interstitial lung diseaseJing Xue0Miaomiao Nian1Yangyang Liang2Zeqin Zhu3Zhenyu Hu4Yuanyuan Jia5Shuhong Chi6Juan Chen7Department of Key Laboratory of Ningxia Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical UniversityNingxia Medical UniversityNingxia Medical UniversityNingxia Medical UniversityNingxia Medical UniversityDepartment of Key Laboratory of Ningxia Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical UniversityDepartment of Rheumatology, General Hospital of Ningxia Medical UniversityDepartment of Key Laboratory of Ningxia Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical UniversityAbstract Background Neutrophil extracellular trap (NET) formation has been implicated as a pathogenic mechanism in both rheumatoid arthritis (RA) and interstitial lung disease (ILD). However, the role of NETs in RA-associated ILD (RA-ILD) and the mechanisms driving NET formation remain unclear. This study aimed to assess the involvement of NETs in RA-ILD and elucidate the underlying mechanisms. Methods Single-cell sequencing was used to identify changes in the quantity and function of neutrophils in the lung tissue of a zymosan A (ZYM)-induced interstitial pneumonia arthritis model. Additionally, nuclear receptor 4A3 (NR4A3) interference was performed in HL-60 cells to assess its impact on NET formation and the transformation of MRC-5 cells into myofibroblasts. The clinical relevance of plasma myeloperoxidase-DNA (MPO-DNA), citrullinated histone 3 (Cit-H3), and cell-free DNA was evaluated in RA-ILD patients with different imaging types via a commercial enzyme-linked immunosorbent assay (ELISA). Results In the ZYM-treated SKG mouse model, which recapitulates key features of RA-ILD, an increased population of neutrophils in the lung tissue was primarily responsible for NET formation. Mechanistically, we found that interference with NR4A3 expression enhanced NET formation in HL-60 cells, which in turn promoted the differentiation of MRC-5 cells into myofibroblasts. Clinically, plasma MPO-DNA levels are elevated in patients with RA-nonspecific interstitial pneumonia (RA-NSIP), whereas Cit-H3 levels are elevated in RA-usual interstitial pneumonia (RA-UIP) patients compared with healthy subjects. ROC curve analysis further revealed that the combination of plasma MPO-DNA, rheumatoid factor (RF), and anti-citrullinated protein (anti-CCP) and the combination of Cit-H3, RF, and anti-CCP were superior diagnostic panels for NSIP and UIP in RA-ILD patients, respectively. Moreover, compared with those from healthy controls, neutrophils from patients with RA-UIP and RA-NSIP demonstrated a significantly increased ability to form NETs and induce the differentiation of MRC-5 cells into myofibroblasts. Specifically, RA-UIP patients exhibited a greater capacity for NET formation and the differentiation of MRC-5 cells into myofibroblasts than did RA-NSIP patients. Conclusions These findings suggest that targeting NETs may be a novel therapeutic approach for treating ILD in RA patients.https://doi.org/10.1186/s12931-025-03111-1Nuclear receptor 4Neutrophil extracellular trapsRheumatoid arthritisInterstitial lung disease |
| spellingShingle | Jing Xue Miaomiao Nian Yangyang Liang Zeqin Zhu Zhenyu Hu Yuanyuan Jia Shuhong Chi Juan Chen Neutrophil extracellular traps (NETs) are increased in rheumatoid arthritis-associated interstitial lung disease Respiratory Research Nuclear receptor 4 Neutrophil extracellular traps Rheumatoid arthritis Interstitial lung disease |
| title | Neutrophil extracellular traps (NETs) are increased in rheumatoid arthritis-associated interstitial lung disease |
| title_full | Neutrophil extracellular traps (NETs) are increased in rheumatoid arthritis-associated interstitial lung disease |
| title_fullStr | Neutrophil extracellular traps (NETs) are increased in rheumatoid arthritis-associated interstitial lung disease |
| title_full_unstemmed | Neutrophil extracellular traps (NETs) are increased in rheumatoid arthritis-associated interstitial lung disease |
| title_short | Neutrophil extracellular traps (NETs) are increased in rheumatoid arthritis-associated interstitial lung disease |
| title_sort | neutrophil extracellular traps nets are increased in rheumatoid arthritis associated interstitial lung disease |
| topic | Nuclear receptor 4 Neutrophil extracellular traps Rheumatoid arthritis Interstitial lung disease |
| url | https://doi.org/10.1186/s12931-025-03111-1 |
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