A team of researchers led by Professor ZHOU Haining at the Institute of Biophysics, Chinese Academy of Sciences (CAS), has identified a distinct macrophage subset, termed ReM2, with a unique phagocytic function that enables it to directly "eat" scar tissue in the liver.

Their findings, published in PNAS, reveal a natural mechanism for reversing liver fibrosis and offer new insights for the treatment of chronic liver disease.

Liver fibrosis, a scarring process underlying most chronic liver diseases, claims nearly two million lives annually with no effective therapy available. Macrophages have long been implicated in this process, but their opposing roles in promoting versus resolving scarring have remained unclear. Using single cell sequencing and spatial mapping in a mouse model, the researchers identified a previously uncharacterized macrophage subset, ReM2, which expresses unique surface receptors-FCGR4 and ITGA4-that enable it to directly recognize and engulf collagen and fibronectin, the main components of scar tissue, distinguishing it from profibrotic scar associated macrophages (SAMs).

"This is a paradigm shift," said ZHOU. "Traditionally, we thought macrophages dissolved scars by releasing degrading enzymes. Instead, ReM2 literally eats the scar through receptor-mediated phagocytosis."

The team proved this mechanism by blocking either FCGR4 or ITGA4 in mice during the recovery phase. In both cases, fibrosis resolution was significantly delayed. Genetic elimination of ITGA4-positive cells produced the same effect-confirming that these receptors are essential for scar clearance.

Remarkably, ReM2 and SAMs share the same origin: both arise from circulating monocytes. Their fates, however, are controlled by different transcription factors-JUNB pushes cells toward SAMs, while ETS1 drives ReM2 formation. This raises the possibility of tipping the balance therapeutically by boosting ReM2 generation.

Importantly, the researchers found a conserved human counterpart in cirrhotic livers, suggesting that this mechanism could be clinically relevant. The study was supported by the National Key Research and Development Program of China and the Natural Science Foundation of China.

Article link: https://doi.org/10.1073/pnas.2611441123

Contact:

ZHOU Haining

Institute of Biophysics, Chinese Academy of Sciences

Email: zhouhaining@ibp.ac.cn

(Reported by Prof. ZHOU Haining's group)