Work

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

Year: 2026

Type: article

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.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.2611441123