REVIEW article
Front. Immunol.
Sec. Systems Immunology
This article is part of the Research TopicMacrophages at the Crossroads of Fibrosis and ImmunosuppressionView all 10 articles
The gene regulatory networks shaping macrophage plasticity and altered function in fibrosis
Provisionally accepted
- 1Department of Surgery, Transplantation and Gastroenterology, Semmelweis Egyetem, Budapest, Hungary
- 2Nuclear Receptor Research Laboratory, Department of Biochemistry and Molecular Biology, Faculty of Medicine, Debreceni Egyetem, Debrecen, Hungary
- 3Departments of Medicine, Pediatrics, Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research and Biomedical Engineering, Johns Hopkins All Children's Hospital, St. Petersburg, United States
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Tissue inflammation and its resolution are fundamental physiological processes that ensure homeostasis and tissue integrity following injury. A precise balance between pro-inflammatory and pro-resolving mechanisms promotes proper tissue repair, whereas dysregulation of these pathways results in chronic damage and fibrosis. This complex multicellular phenomenon ultimately manifests in extensive extracellular matrix (ECM) deposition and organ failure. Although the core transcriptional programs are highly conserved throughout evolution and across different species and tissues, distinct features arise under the influence of specific tissue microenvironments. The functionally divergent phenotypes and widespread heterogeneity of macrophages enable them to play a key modulatory role along the inflammation–resolution–fibrosis axis. Recent advances in epigenetic and transcriptomic profiling have revealed novel regulatory circuits and candidate transcriptional regulators governing macrophage phenotypes in fibrotic contexts. In this review, we aim to integrate current knowledge on the complex, context-dependent regulatory mechanisms and dysfunction of macrophages in fibrosis. We highlight the importance of macrophage ontogeny, signal-and metabolism-dependent transcriptional regulation, and chromatin remodeling in disease progression, with particular attention to therapeutic perspectives.
Keywords: Fibrosis3, macrophage dysfunction2, macrophage plasticity1, tissue microenvironment6, tissue remodeling5, transcriptional reprogramming4
Received: 15 Dec 2025; Accepted: 09 Feb 2026.
Copyright: © 2026 Kolostyak and Nagy. 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: Laszlo Nagy
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