Iguratimod improves bleomycin-induced pulmonary inflammation and fibrosis by regulating macrophage polarization through inhibiting the TLR4/NF-κB pathway

Xu, Huan; Ma, Kaixuan; Ma, Ziting; Zhuang, Tianyu; Lin, Ling

doi:10.3389/fimmu.2025.1558903

ORIGINAL RESEARCH article

Front. Immunol.

Sec. Inflammation

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1558903

This article is part of the Research Topic Harnessing Big Data for Precision Medicine: Revolutionizing Diagnosis and Treatment Strategies View all 29 articles

Iguratimod improves bleomycin-induced pulmonary inflammation and fibrosis by regulating macrophage polarization through inhibiting the TLR4/NF-κB pathway

Provisionally accepted

Huan Xu

Kaixuan Ma

Ziting Ma

Tianyu Zhuang

Ling Lin ^*

First Affiliated Hospital of Shantou University Medical College, Shantou, China

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

Pulmonary fibrosis (PF) is a fatal pathological subtype of interstitial lung disease, frequently manifests as a pulmonary complication of connective tissue disease. Iguratimod (IGU) is a new class of anti-rheumatic drugs used in the treatment of rheumatoid arthritis (RA). Studies have reported that RA patients treated with IGU have better lung function, and IGU effectively ameliorates PF. However, the mechanism by which IGU improves PF is still unclear. This study aims to elucidate the therapeutic efficacy and mechanisms of IGU in PF through in vivo and in vitro investigations, so as to provide a new treatment method for PF. In our research, bleomycin (BLM)-induced PF of mice were used to observe the therapeutic effect of different concentrations of IGU. And the effects of IGU on macrophage polarization and activation pathway TLR4/NF-κB in lung tissue were analyzed. In addition, Raw264.7 macrophages were induced to M1 and M2 polarization in vitro, and the effects of IGU on Raw264.7 macrophage polarization and related pathways were observed. In our study, database analysis suggested that macrophage polarization-relative genes and pathways as well as TLR4 activation played important roles in BLM-induced PF in mice. Besides, we found that IGU effectively ameliorated BLM-induced PF and epithelial-mesenchymal transition in mice, and inhibited the polarization of M1/M2 macrophages at different stages of PF. Moreover, In vitro studies further demonstrated that IGU suppressed M1 polarization of Raw264.7 and its activation pathway TLR4/NF-κB. In summary, IGU inhibits the activation of macrophages and M1 polarization through inhibiting the TLR4/NF-κB pathway, thereby improving BLM-induced pulmonary inflammation and fibrosis in mice. It is suggested that IGU may be a new therapeutic option for interstitial pulmonary fibrosis.

Keywords: Interstitial pulmonary fibrosis, Inflammation, Iguratimod, M1 polarization, TLR4

Received: 11 Jan 2025; Accepted: 28 Feb 2025.

Copyright: © 2025 Xu, Ma, Ma, Zhuang and Lin. 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: Ling Lin, First Affiliated Hospital of Shantou University Medical College, Shantou, China

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