Chemical Tag on mRNA Supercharges Scavenger Cells to Heal Dangerous Liver Abscesses

A single chemical tag on a strand of messenger RNA may determine whether a life-threatening liver infection heals or spirals into sepsis, according to a new study published in Immunity, Inflammation and Disease. Researchers report that boosting an enzyme called METTL3, which decorates mRNA molecules with N6-methyladenosine (m6A) marks, dramatically improved recovery in mice with bacterial liver abscesses. The improvement worked through an unexpected route: it reprogrammed macrophages, the immune system’s professional scavengers, into more efficient cleaners of dead and dying cells. The finding exposes a previously underappreciated epitranscriptomic switch that governs how inflammation is actively resolved, rather than merely suppressed, in infected tissue.

Liver abscess is a severe suppurative infection in which pockets of pus and necrotic debris accumulate within hepatic tissue. The core pathological problem, the authors note, is not simply the presence of bacteria but the failure to promptly clear the large amounts of dead cells and pathogen fragments left behind at the infection site. That debris sustains an excessive and persistent inflammatory response, worsening local tissue damage and eroding clinical prognosis. Left unchecked, the process can progress to peritonitis and sepsis, causing irreversible and potentially fatal injury. Current standard treatments, antibiotics and percutaneous drainage, are effective at eliminating pathogens and managing the abscess cavity, but they do little to strengthen the body’s intrinsic capacity to calm inflammation, and some patients respond poorly, particularly when initial treatment is delayed.

At the center of the new work is efferocytosis, the process by which macrophages recognize, engulf, and digest apoptotic and necrotic cells. Efferocytosis is far more than housekeeping: as macrophages consume cellular corpses, they are pushed toward an anti-inflammatory and reparative phenotype, releasing mediators that actively resolve inflammation and initiate tissue reconstruction. Under the high-burden infectious stress of a liver abscess, however, this scavenging function is often suppressed or impaired, creating a vicious cycle in which necrotic debris accumulates, inflammation persists, and tissue damage compounds. Enhancing efferocytosis, the researchers argue, is therefore a key scientific challenge for promoting genuine healing of abscessed liver lesions rather than merely containing them.

To find a lever for that enhancement, the team looked to Nrf2, a central transcription factor in cellular anti-inflammatory defense that is known to maintain macrophage functional homeostasis and regulate phagocytosis-related genes. The upstream mechanisms controlling Nrf2 expression in liver abscess had not been elucidated. The investigators focused on m6A, the most abundant internal chemical modification of eukaryotic mRNA, which is catalyzed by methyltransferases such as METTL3 and dynamically regulates target genes by influencing mRNA stability, splicing, nuclear export, and translation efficiency. Whether METTL3-mediated m6A methylation of Nrf2 mRNA could serve as a regulatory node for macrophage efferocytosis under infectious stress was the central question of the study.

The experimental design combined a mouse model with cell culture rescue experiments. Forty male SPF-grade C57BL/6J mice were randomly assigned to control, bacterial liver abscess model, abscess plus control vector, and abscess plus METTL3 overexpression groups. After receiving adeno-associated virus vectors via tail vein injection four weeks before modeling, the animals underwent intrahepatic injection of Klebsiella pneumoniae, the leading clinical cause of liver abscess, accounting for more than half of isolates. All live-pathogen procedures were conducted under Biosafety Level 2 conditions. The model was validated by significant weight loss, pathological liver damage, and elevated serum inflammatory cytokines, while fluorescence imaging confirmed successful hepatic delivery of the vectors.

The gross and microscopic results were striking. Livers from untreated abscess mice appeared dark red with multiple firm, whitish round protrusions of one to two millimeters along the lobular margins, occasionally coalescing into larger lesions, together with regional yellowish abscesses and histological evidence of hepatocyte necrosis, inflammatory infiltration, and fibroblast proliferation. In mice overexpressing METTL3, the focal protrusions were noticeably fewer and hepatic tissue damage was significantly attenuated. Serum analysis reinforced the picture: overexpression lowered the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α while raising the anti-inflammatory, pro-resolution mediators IL-10 and TGF-β. The authors interpret this bidirectional shift as evidence that METTL3 redirected the inflammatory milieu toward resolution and repair rather than inducing nonspecific immunosuppression.

Molecular profiling revealed the mechanism underneath. METTL3 overexpression increased m6A enrichment on Nrf2 mRNA, as measured by methylated RNA immunoprecipitation followed by quantitative PCR, and further activated the Nrf2/HO-1 signaling axis, elevating Nrf2 and HO-1 protein levels while suppressing the negative regulator Keap-1. Downstream, the expression of the TAM receptor family, MerTK, Tyro3, and AXL, rose significantly in the livers of abscess mice and climbed higher still with METTL3 overexpression. These receptors form the molecular machinery of efferocytosis: MerTK directly drives clearance of apoptotic and necrotic cells and promotes reparative macrophage polarization, while AXL and Tyro3 fine-tune immune homeostasis. Immunofluorescence co-localization showed that F4/80-positive hepatic macrophages co-expressing MerTK and Nrf2 increased in the abscess model and increased further with METTL3, linking Nrf2 activation spatially to enhanced efferocytic capacity.

Causality was established in LPS-stimulated RAW264.7 macrophages using a four-group design crossing METTL3 overexpression with Nrf2-targeting siRNA. METTL3 overexpression markedly increased mRNA and protein levels of all three TAM receptors and shifted the macrophage phenotype, reducing the proportion of CD86-positive pro-inflammatory cells and increasing CD206-positive anti-inflammatory, pro-repair cells. Nrf2 knockdown reversed every one of these effects, and two-way ANOVA confirmed significant interactions between the two manipulations for MerTK, Tyro3, and AXL expression as well as for polarization markers. The rescue experiments establish Nrf2 as the key downstream mediator through which METTL3 promotes an anti-inflammatory, pro-efferocytic macrophage state, consistent with prior evidence that Nrf2/HO-1 signaling regulates MerTK expression and that Nrf2 deficiency impairs apoptotic-cell clearance.

The study situates itself within a growing literature showing that METTL3’s role is context-dependent. It promotes post-infarction inflammation after myocardial infarction, exacerbates renal tubular inflammation and inflammatory bowel disease, yet its knockdown worsens neuroinflammation in hyperuricemic mice. In the abscess model, endogenous METTL3 rose alongside inflammatory cytokines, suggesting it may act as a compensatory protector early in disease, and its deliberate overexpression exerted therapeutic anti-inflammatory effects. The authors are candid about limitations: the TBG-driven AAV induced hepatic rather than macrophage-specific overexpression, rescue experiments used a macrophage cell line rather than primary Kupffer cells, direct apoptotic-cell engulfment assays and Nrf2 promoter-binding experiments were not performed, and the work covered a single bacterial strain and one terminal time point. Future studies with macrophage-specific genetic models, ChIP-qPCR, and m6A site mapping are planned. Even so, the METTL3/Nrf2 axis now stands as a compelling candidate target for therapies that would help patients resolve liver abscess inflammation from within, complementing antibiotics and drainage rather than replacing them.

Subject of Research: METTL3-mediated m6A methylation of Nrf2 mRNA regulating macrophage efferocytosis in bacterial liver abscess

Article Title: METTL3 Alleviates Liver Abscess by Enhancing Macrophage Efferocytosis via m6A Methylation of Nrf2 mRNA

Article References: Wang, G., Luo, D., Pang, Y., Gao, C., Jin, D., & Wang, Q. (2026). METTL3 Alleviates Liver Abscess by Enhancing Macrophage Efferocytosis via m 6 A Methylation of Nrf2 mRNA. Immunity, Inflammation and Disease, 14(10), Article e70534. https://doi.org/10.1002/iid3.70534

Image Credits: AI Generated

DOI: 10.1002/iid3.70534

Keywords: METTL3, m6A methylation, Nrf2, efferocytosis, macrophages, liver abscess, Klebsiella pneumoniae, TAM receptors, MerTK, inflammation resolution, epitranscriptomics, HO-1