VSIG4+ macrophages interrupt CCL2-CCR2 inflammatory amplification to mitigate acetaminophen-induced acute liver injury

Acute liver injury (ALI) can rapidly progress to life-threatening acute liver failure (ALF), with liver transplantation being the only definitive treatment despite severe donor shortages. Macrophage-based therapies show promise for ALI, but current approaches lack precision in targeting specific macrophage subsets. While VSIG4 is known as a marker for resident Kupffer cells, its role in monocyte-derived macrophages (MoMFs) during ALI, and its potential therapeutic utility, remained largely unexplored, representing a critical gap in understanding and treatment.

Researchers integrated single-cell RNA sequencing (scRNA-seq) data from human and mouse liver tissues with clinical ALI samples to characterize VSIG4+ macrophages. They developed a reversible immunomagnetic nanoparticle system to isolate viable VSIG4+ Mφ non-destructively. The therapeutic efficacy and mechanisms of these isolated cells were then evaluated in an acetaminophen (APAP)-induced ALI mouse model. Additionally, a vascularized human liver organoid ALI model and a monocyte chemotaxis model were established to further validate findings and explore mechanisms, comparing VSIG4+ MoMFs transfer against unselected bone marrow-derived macrophages (BMDM).

Single-cell RNA sequencing revealed a previously unrecognized subpopulation of VSIG4+ monocyte-derived macrophages (MoMFs) that significantly increased following ALI, contrasting with a decrease in resident VSIG4+ Kupffer cells. Clinical ALI tissue samples further confirmed the presence of CCR2+VSIG4+ cells in patient livers. In the APAP-induced ALI animal model, adoptive transfer of isolated VSIG4+ MoMFs dramatically decreased serum alanine transaminase, hepatic necrosis, and apoptosis, while concurrently increasing anti-inflammatory cytokines. In stark contrast, adoptive transfer of unselected BMDM failed to improve liver injury and instead exacerbated certain pro-inflammatory responses, including elevated TNF-α and reduced CD206 expression. Mechanistically, VSIG4+ MoMFs prevented inflammatory amplification.

They achieved this by suppressing NF-κB-dependent CCL2 transcription, thereby effectively disrupting the CCL2-CCR2 chemotactic axis.