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May 20, 2026

B77-04 Atp-p2x4/p2x7 Signalling Drives Monocyte Cytokine Activation in Progressive Fibrotic Lung Disease and Is Attenuated by Nintedanib

LFL FordeRoyal College of Surgeons in Ireland DGD GogoiRoyal College of Surgeons in Ireland RBR BairdRoyal College of Surgeons in Ireland

Key Points

This study investigates how P2X4/P2X7 signaling drives cytokine activation in progressive fibrotic lung disease and the impact of nintedanib on this process.
Analyzed P2X receptor expression in monocytes from healthy controls and untreated or nintedanib-treated fibrotic lung disease patients (total n=48).
Measured plasma IL-1β and TNFR1 levels using ELISA and performed ex vivo stimulation with ATP and TNF-alpha.
Statistical comparisons were made using the Mann-Whitney U test.
Monocytes in untreated fibrotic lung disease showed significantly elevated P2X4 and P2X7 expression.
IL-1β and TNFR1 levels were higher in untreated patients compared to healthy controls, with p < 0.0001.
Nintedanib treatment led to significantly lower levels of IL-1β (p = 0.0008) and TNFR1 (p = 0.002).

Abstract

Abstract Rationale Circulating monocytes contribute to inflammation in progressive fibrotic lung disease (IPF/PPF), but upstream drivers of cytokine release remain poorly defined. Extracellular ATP acts as a danger signal via ionotropic P2X receptors. We investigated purinergic receptor expression, ATP-driven cytokine induction, receptor inhibition, and the effect of nintedanib on monocyte activation. Methods Peripheral blood monocytes and plasma were obtained from healthy controls (HC; n = 20), untreated IPF/PPF (n = 20), and IPF/PPF receiving nintedanib (n = 8). P2X receptor expression was quantified by RT-qPCR and Western blot. Plasma IL-1β and TNFR1 were measured by ELISA. Monocytes were stimulated ex vivo with ATP and/or TNF-alpha using time-course analysis, with selective P2X4/P2X7 inhibition. Statistical comparisons used the Mann-Whitney U test. Results Monocytes from IPF/PPF patients demonstrated significantly increased P2X4 and P2X7 expression at mRNA and protein levels compared with HC. Plasma IL-1β (p 0.0001) and TNFR1 (p 0.0001) were elevated in untreated disease. Patients receiving nintedanib exhibited significantly lower IL-1β (p = 0.0008) and TNFR1 (p = 0.002). Baseline monocyte IL-1β production was elevated in IPF/PPF compared with HC. ATP stimulation induced a time-dependent increase in IL-1β protein abundance, with greater magnitude in IPF/PPF monocytes than HC. Combined ATP and TNF-alpha stimulation synergistically amplified IL-1β expression. Selective inhibition of P2X4 and P2X7 attenuated ATP-induced cytokine release. Across endpoints, untreated disease showed heightened baseline cytokine production and exaggerated ATP responsiveness. Conclusions Circulating monocytes in fibrotic lung disease display upregulated P2X4/P2X7 expression and exaggerated ATP-driven cytokine release, amplified by TNF-alpha synergy. Receptor-selective inhibition attenuates this response, indicating a key upstream checkpoint in monocyte activation. Nintedanib reduces circulating cytokines and dampens ATP-induced responses, suggesting an additional immunomodulatory action beyond antifibrotic activity. These data highlight a therapeutically targetable inflammatory axis with relevance to patient treatment and pathway-guided intervention. This abstract is funded by: Bons Secours, Dublin

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