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

PNAS, 21 August, 2026, DOI：https://doi.org/10.1073/pnas.2611441123

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

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

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.

文章链接：https://www.pnas.org/doi/10.1073/pnas.2611441123

相关报道：https://www.ibp.cas.cn/jz/zxdt/202608/t20260831_8267349.html