What does this research mean for the field?

The IL-33/ST2/AREG axis mediates a pathogenic ST2+ regulatory T cell response that promotes lung fibrosis in rheumatoid arthritis-associated interstitial lung disease. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This study aims to clarify the role of ST2+ regulatory T cells in the progression of RA-associated interstitial lung disease.

May 30, 2026Open Access

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

Key Points

This study aims to clarify the role of ST2+ regulatory T cells in the progression of RA-associated interstitial lung disease.
Developed a murine model of collagen-induced arthritis with bleomycin administration to simulate RA-ILD features.
Analyzed a clinical cohort of healthy controls, RA patients without ILD, and RA patients with ILD using flow cytometry and HRCT imaging.
Performed histopathological assessments of lung inflammation and fibrosis in the murine model.
Flow cytometry revealed expansion of ST2+ Tregs in both murine model and peripheral blood of RA-ILD patients.
Quantitative HRCT analysis showed a positive correlation between ST2+ Treg frequency and lung fibrosis severity in patients.
Elevated serum levels of IL-33 and AREG were found in RA-ILD patients, correlating with increased disease severity.

Abstract

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. 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). 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. 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.

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