Macrophages diverge into profibrotic SAMs and proresolving ReM2 cells to regulate liver fibrosis.

Authors

Dezhen Zhang, Xinjie Liu, Dong Ma, Lingling Liao, Fugang Duan, Yiming Wang, Tongzhen Zhang, Jiang Liu, Wei Dong, Junfei Jin, Zhenhua Luo, Haining Zhou

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 34. Pages e2611441123. Aug 25, 2026. Epub Aug 21, 2026.

Abstract

A central question in liver fibrosis is how macrophages, key regulators of inflammation and tissue repair, are divergently programmed to either promote scar formation or drive its resolution. Here, we identify a macrophage axis that governs this balance. While scar-associated macrophages (SAMs) promote fibrogenesis through cytokine-mediated activation of hepatic stellate cells, a previously uncharacterized macrophage subset, termed ReM2, orchestrates fibrosis regression. ReM2 arises from circulating monocytes following liver injury, accumulates during fibrogenesis, and peaks during the resolution phase. Mechanistically, ReM2-dependent fibrosis regression requires the expression of specific receptors, including FCGR4 and ITGA4, which may mediate this effect by enabling direct recognition and phagocytic clearance of collagen I and fibronectin from the extracellular matrix. These findings reveal a functional divergence of monocyte-derived macrophages that governs fibrosis progression vs. resolution and suggest that therapeutic rebalancing of the SAM-ReM2 axis may represent a promising strategy for treating liver fibrosis.

PMID:
42627827
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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