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Background <p>Interstitial lung disease (ILD) represents a significant extra-articular complication associated with rheumatoid arthritis (RA), contributing substantially to the morbidity and mortality observed in affected patients. Despite its clinical relevance, the underlying mechanisms driving the pathogenesis of RA-ILD remain poorly understood, necessitating further investigation into the immunological factors that may play a role in this condition.</p> Methods <p>This study aimed to elucidate the role of ST2<sup>+</sup> regulatory T cells (Tregs) in the progression of RA-ILD. To achieve this, we developed a composite murine model that integrated collagen-induced arthritis (CIA) with intratracheal bleomycin (BLM) administration, thereby simulating the pathophysiological features of RA-ILD. Concurrently, using flow cytometric and artificial intelligence-based quantitative analysis of high-resolution computed tomography (HRCT), we analyzed a clinical cohort consisting of healthy controls, RA patients without ILD (RA-nonILD), and RA patients with ILD (RA-ILD).</p> Results <p>Histopathological assessment confirmed that the composite model exhibited exacerbated lung inflammation and fibrosis. Notably, flow cytometry revealed a marked expansion of ST2<sup>+</sup> Tregs in both the lungs of CIA + BLM mice and the peripheral blood of RA-ILD patients. Moreover, quantitative HRCT analysis indicated a positive correlation between the frequency of ST2<sup>+</sup> Tregs and fibrotic lung volume in patients. RA-ILD patients exhibited elevated serum levels of IL-33 and amphiregulin (AREG), which correlated with disease severity. In vitro studies further demonstrated that IL-33 stimulation significantly upregulated AREG expression at both the mRNA and protein levels in Tregs.</p> Conclusion <p>These results highlight the potential involvement of the IL-33/ST2 axis in mediating a pathogenic Tregs response characterized by AREG production, thereby linking systemic autoimmunity to the progression of lung fibrosis in RA-ILD. Importantly, this study identifies the IL-33/ST2/AREG axis and ST2<sup>+</sup> Tregs as promising biomarkers and therapeutic targets for RA-ILD, laying the groundwork for future mechanistic studies and translational research endeavors.</p>

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Elevated ST2+ Tregs in RA-ILD: correlation with pulmonary fibrosis and the IL-33/ST2/AREG axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • Peiyan Zhang,
  • Jiawei Wang,
  • Haoyang Sun,
  • Jinlin Miao,
  • Zhaohui Zheng

摘要

Background

Interstitial lung disease (ILD) represents a significant extra-articular complication associated with rheumatoid arthritis (RA), contributing substantially to the morbidity and mortality observed in affected patients. Despite its clinical relevance, the underlying mechanisms driving the pathogenesis of RA-ILD remain poorly understood, necessitating further investigation into the immunological factors that may play a role in this condition.

Methods

This study aimed to elucidate the role of ST2+ regulatory T cells (Tregs) in the progression of RA-ILD. To achieve this, we developed a composite murine model that integrated collagen-induced arthritis (CIA) with intratracheal bleomycin (BLM) administration, thereby simulating the pathophysiological features of RA-ILD. Concurrently, using flow cytometric and artificial intelligence-based quantitative analysis of high-resolution computed tomography (HRCT), we analyzed a clinical cohort consisting of healthy controls, RA patients without ILD (RA-nonILD), and RA patients with ILD (RA-ILD).

Results

Histopathological assessment confirmed that the composite model exhibited exacerbated lung inflammation and fibrosis. Notably, flow cytometry revealed a marked expansion of ST2+ Tregs in both the lungs of CIA + BLM mice and the peripheral blood of RA-ILD patients. Moreover, quantitative HRCT analysis indicated a positive correlation between the frequency of ST2+ Tregs and fibrotic lung volume in patients. RA-ILD patients exhibited elevated serum levels of IL-33 and amphiregulin (AREG), which correlated with disease severity. In vitro studies further demonstrated that IL-33 stimulation significantly upregulated AREG expression at both the mRNA and protein levels in Tregs.

Conclusion

These results highlight the potential involvement of the IL-33/ST2 axis in mediating a pathogenic Tregs response characterized by AREG production, thereby linking systemic autoimmunity to the progression of lung fibrosis in RA-ILD. Importantly, this study identifies the IL-33/ST2/AREG axis and ST2+ Tregs as promising biomarkers and therapeutic targets for RA-ILD, laying the groundwork for future mechanistic studies and translational research endeavors.