Dissecting the liver inflammation ecosystem identifies annexin A1 as a pro-resolving target for liver failure

Acute-on-chronic liver failure (ACLF) is driven by systemic inflammation and immune dysregulation. This study aims to characterize the immune landscape in ACLF and identify potential therapeutic targets.

We employed single-cell RNA sequencing, vision spatial sequencing, bulk RNA sequencing, and bioinformatics analysis to profile immune cells in ACLF livers compared to acute liver failure, decompensated cirrhosis, and controls. ACLF livers exhibited a distinct immune signature with increased neutrophils, particularly CCL4 + subsets, which drive unresolved inflammation by recruiting additional neutrophils and inflammatory CD14 + S100A9 + monocytes. Resident KCs were reduced, and monocytes differentiated into TREM2 + macrophages with an M1-like pro-inflammatory phenotype, exacerbating inflammation. Additionally, lymphoid cells showed significant dysfunction, with reduced NK cells and relatively expanded T cells exhibiting diminished cytotoxicity or pro-inflammatory cytokine production. Cell-cell communication analysis identified the ANXA1-FPR1 axis as a key interaction between T cells and myeloid cells, serving as a negative feedback mechanism to dampen inflammation. Plasma and hepatic ANXA1 levels were elevated in ACLF patients, correlating with disease severity. In the preclinical model, the ANXA1 peptide Ac2-26 improved liver function, reduced inflammation, and promoted macrophage polarization from M1 to M2. In vitro, Ac2-26 inhibited CCL4-mediated monocyte chemotaxis and M1 polarization, effects partially blocked by the FPR1 inhibitor Randialic acid B. Mechanically, Ac2-26 activated AMPK and inhibited mTOR signaling.

Our findings provide a comprehensive immune profile in ACLF and highlight ANXA1 as a potential therapeutic target for resolving immune dysregulation and improving outcomes in ACLF.