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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Molecular Innate Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1480594

"Neutrophil Extracellular Traps as immunofibrotic mediators in RA-ILD; Pilot evaluation of the nintedanib therapy"

Provisionally accepted
Aliki I. Venetsanopoulou Aliki I. Venetsanopoulou 1Maria Ntinopoulou Maria Ntinopoulou 2Eleni Papagianni Eleni Papagianni 2Nikolaos Koletsos Nikolaos Koletsos 1Paraskevi Voulgari Paraskevi Voulgari 1Akrivi Chrysanthopoulou Akrivi Chrysanthopoulou 2*
  • 1 Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece
  • 2 Laboratory of Molecular Immunology, Department of Biological Applications and Technology, School of Health Sciences, University of Ioannina, Ioannina, Greece

The final, formatted version of the article will be published soon.

    Objective: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a significant pulmonary complication of RA. This study tried to elucidate the mechanisms enhancing inflammation and causing lung injury in RA-ILD, focusing on the role of neutrophil extracellular traps (NETs). The study also investigated the potential benefits of nintedanib in advanced disease.Methods: Nine RA-ILD patients and nine healthy controls were included in the study.Inflammatory markers in patients' circulation were evaluated with immunoassays. The formation of NETs was examined using a citrullinated histone H3 (CitH3) ELISA and cell immunofluorescence. Inflammatory proteins expressed in neutrophils/NETs were studied with real-time qPCR and NET ELISA. To assess the effect of nintedanib, an intracellular tyrosine kinase inhibitor with antifibrotic properties, in RA-ILD a paired study was conducted in five patients before treatment administration and 16 weeks later.The soluble terminal complement complex sC5b-9 and the levels of CitH3 were significantly elevated in patients with RA-ILD, compared to healthy controls. In addition, neutrophils isolated from RA-ILD patients released NETs enriched with tissue factor and interleukin-17A. Inflammatory NETs had a dynamic role, increasing the fibrotic potential of human pulmonary fibroblasts (HPFs). On the other hand, nintedanib treatment decreased NETs and sC5b-9 levels in RA-ILD patients.The findings propose an interplay between circulating NETs and HPFs, establishing the immunofibrotic aspects of RA-ILD. They also support the effectiveness of nintedanib in reducing key pathological processes of the disease. Further research is needed to fully understand these mechanisms and optimize treatment strategies for RA-ILD.

    Keywords: rheumatoid arthritis-interstitial lung disease, neutrophil extracellular traps, Interleukin-17A, tissue factor, Terminal complement complex, Fibroblasts, Nintedanib

    Received: 14 Aug 2024; Accepted: 30 Sep 2024.

    Copyright: © 2024 Venetsanopoulou, Ntinopoulou, Papagianni, Koletsos, Voulgari and Chrysanthopoulou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Akrivi Chrysanthopoulou, Laboratory of Molecular Immunology, Department of Biological Applications and Technology, School of Health Sciences, University of Ioannina, Ioannina, Greece

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.