Expansion of distinct peripheral blood myeloid cell subpopulations in patients with rheumatoid arthritis-associated interstitial lung disease

Poole, Jill A.; Cole, Kathryn E.; Thiele, Geoffrey M.; Talmadge, James E.; England, Bryant R.; Nelson, Amy J.; Gleason, Angela; Schwab, Aaron; Gaurav, Rohit; Duryee, Michael J.; Bailey, Kristina L.; Romberger, Debra J.; Hershberger, Daniel; De Graaff, Joel Van; May, Sara M.; Walenz, Rhonda; Kramer, Bridget; Mikuls, Ted R.

doi:10.1016/j.intimp.2023.111330

Cited by 4 publications

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Unique transcriptomic profile of peripheral blood monocytes in rheumatoid arthritis-associated interstitial lung disease

Poole,

Schwab,

Thiele

et al. 2024

Rheumatology

View full text Add to dashboard Cite

Objectives Though interstitial lung disease (ILD) contributes to excess morbidity and mortality in rheumatoid arthritis (RA), RA-ILD pathogenesis remains incompletely defined. As intermediate, non-classical and suppressed CD14+ monocytes are expanded in RA-ILD, this study sought to characterize gene expression profiles of circulating monocytes in RA-ILD. Methods Peripheral blood mononuclear cells were collected from patients with RA without lung disease (N = 5), RA-ILD (N = 5), idiopathic pulmonary fibrosis (IPF; N = 5), and controls without lung and autoimmune disease (N = 4). RNA was extracted from CD14+ isolated monocytes and subjected to transcriptional analysis of 1365 genes. Gene enrichment and pathway analyses were performed. Results Unsupervised clustering grouped patients with RA-ILD together with IPF for myeloid innate genes. For fibrosis genes, patients with RA-ILD clustered independent of comparator groups. There were 103, 66, and 64 upregulated and 66, 14, and 25 downregulated genes for RA-ILD, RA, and IPF, vs controls, respectively. For RA-ILD, there was increased expression of genes involved in regulating inflammation and fibrosis (SOCS3, CECAM1, LTB4R2, CLEC7A, IRF7, PHYKPL, GBP5, RAPGEF), epigenetic modification (KDM5D, KMT2D, OGT), and macrophage activation. Top canonical pathways included macrophage differentiation-activation, IL-12, neuroinflammatory, glucocorticoid receptor, and IL-27 signalling. Conclusions Circulating monocytes in RA-ILD patients demonstrate unique gene expression profiles with innate immune gene features more aligned with IPF as opposed to RA in the absence of clinical lung disease with fibrosis gene expression that was distinct from RA and IPF. These studies are important for understanding disease pathogenesis and may provide information for future therapeutic targets in RA-ILD.

show abstract

Unique transcriptomic profile of peripheral blood monocytes in rheumatoid arthritis-associated interstitial lung disease

Poole,

Schwab,

Thiele

et al. 2024

Rheumatology

View full text Add to dashboard Cite

show abstract

Neutrophil dynamics in pulmonary fibrosis: pathophysiological and therapeutic perspectives

Crowley,

Stockley,

Thickett

et al. 2024

Eur Respir Rev

View full text Add to dashboard Cite

The shared pathobiological mechanisms driving progressive fibrosis in interstitial lung diseases (ILDs) remain unclear. Neutrophils, the most common immune cells in the human body, contain an extensive array of proteinases that are important for cell function, including tissue repair and remodelling. Increasing observational studies have reported elevated neutrophil counts in the respiratory tract and circulation of patients with ILD and suggest a role as a biomarker of disease severity. Neutrophils and their contents (including the formation of neutrophil extracellular traps (NETs)) are present in fibrotic lung tissue. Proteinases and NETs may drive fibrogenesis in animal andin vitromodels and may impact transforming growth factor-β1 activation. However, the effect of neutrophil action, whether reparative or pathologically destructive to the delicate lung architecture, has yet to be determined. This review aims to summarise the current literature surrounding the potential role of the neutrophil as a biomarker and contributor to the pathogenesis of ILD. There is currently a paucity of treatment options in ILD driven by the knowledge gap underlying the overall disease mechanisms. This review concludes that neutrophils warrant further evaluation as manipulation of recruitment and function could provide a novel and much needed therapeutic strategy.

show abstract

Neutrophil extracellular traps are involved in the occurrence of rheumatoid arthritis-associated interstitial lung disease

Xue,

Nian,

Zhu

et al. 2024

Preprint

View full text Add to dashboard Cite

Background The excessive formation of neutrophil extracellular traps (NETs) has been demonstrated to be a pathogenic mechanism in both rheumatoid arthritis (RA) and interstitial lung disease (ILD). However, whether NETs contribute to RA-associated ILD (RA-ILD) and the underlying mechanisms driving NETs 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, along with the detection of NETs components in the lung tissues. Additionally, nuclear receptor 4A3 (NR4A3) expression in HL-60 cells was interfered with to detect the effects on NETs components 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 patients with RA-nonspecific interstitial pneumonia (NSIP) and RA-usual interstitial pneumonia (UIP), RA-organizing pneumonia (OP), RA-other patterns, and healthy cohorts using commercial enzyme-linked immunosorbent assay (ELISA). Results In the ZYM-treated SKG mouse model, which recapitulates key features of RA-ILD, an increased neutrophils population in lung tissue was primarily responsible for NETs formation. Mechanistically, interference with NR4A3 expression was found to promoted NETs formation in HL-60 cells, subsequently enhancing MRC-5 cell differentiation into myofibroblasts. Clinically, plasma levels of MPO-DNA and Cit-H3 were elevated in patients with RA-NSIP and RA-UIP compared to healthy subjects. ROC curve analysis further revealed that plasma MPO-DNA combined with RF and anti-CCP, as well as Cit-H3 combined with RF and anti-CCP, served as superior diagnostic panels for NSIP and UIP in RA-ILD patients, respectively. Conclusions These findings suggest that targeting NETs could provide a novel therapeutic approach for ILD in RA patients.

show abstract

Expansion of distinct peripheral blood myeloid cell subpopulations in patients with rheumatoid arthritis-associated interstitial lung disease

Cited by 4 publications

References 54 publications

Unique transcriptomic profile of peripheral blood monocytes in rheumatoid arthritis-associated interstitial lung disease

Unique transcriptomic profile of peripheral blood monocytes in rheumatoid arthritis-associated interstitial lung disease

Neutrophil dynamics in pulmonary fibrosis: pathophysiological and therapeutic perspectives

Neutrophil extracellular traps are involved in the occurrence of rheumatoid arthritis-associated interstitial lung disease

Contact Info

Product

Resources

About