REVIEW article
Front. Immunol.
Sec. Immunological Tolerance and Regulation
This article is part of the Research TopicAdaptive Immune Regulation of Non-Alcoholic Steatohepatitis (NASH)View all 7 articles
Macrophage-Tregs crosstalk: The "hub" of the immune network in MASLD
Provisionally accepted
- 1Hubei University of Chinese Medicine, Wuhan, China
- 2The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- 3Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China
- 4Wuhan No 1 Hospital, Wuhan, China
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Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally prevalent metabolic disorder with a high average worldwide prevalence. It occurs more frequently in men than in women, and its incidence increases with age. MASLD can progressively advance to liver fibrosis, cirrhosis, and even hepatocellular carcinoma, while also elevating the risk of cardiovascular, renal, and other systemic diseases. Its pathological progression is closely associated with dysregulation of the hepatic immune microenvironment, in which aberrant crosstalk between Macrophages (Mø) and regulatory T cells (Tregs) serves as a central driving mechanism. Under physiological conditions, liver-resident Macrophages (Kupffer cells, KCs) and Tregs maintain immune homeostasis through a "complementary origin–spatial co-localization-molecular crosstalk" mechanism. In MASLD, KCs numbers decline while monocyte-derived Macrophages (MDMs) are abnormally recruited, giving rise to Macrophages with distinct phenotypes. Tregs influence the classical phenotypic differentiation of Macrophages. However, dynamic alterations in Treg abundance exhibit a "double-edged sword" effect. The disrupted crosstalk between KCs and Tregs involves dysregulated chemokine networks (e.g., c-x-c motif chemokine ligand 9 (CXCL9), c-c motif chemokine ligand 2 (CCL2)), cytokine interactions (e.g., interleukin-1β (IL-1β), transforming growth factor-Beta (TGF-β)), and signaling pathways such as beta-catenin (β-catenin) and notch homolog 1 (Notch1). Collectively, these alterations drive disease progression from steatosis to hepatitis and fibrosis. This review systematically summarizes the physiological mechanisms underlying Macrophages -Tregs crosstalk, its pathological dysregulation in MASLD, and the associated molecular networks, while proposing targeted therapeutic strategies based on disease stage.
Keywords: macrophage, regulatory T cells, MASLD, crosstalk, Kupffer Cells
Received: 06 Aug 2025; Accepted: 13 Nov 2025.
Copyright: © 2025 Zhao, Wang, Zhu and Shi. 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: Zhaohong Shi, shizhaohong2024@163.com
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