SAA/FPR2 Signaling Between Pericentral Hepatocytes and Macrophages Exacerbates Zonated Liver Transplant Injury

Area of Science:

• Immunology
• Hepatology
• Transplantation Biology

Background:

• Liver transplantation (LT) grafts are susceptible to ischemia-reperfusion injury (HIRI), particularly affecting the pericentral zone.
• The precise mechanisms driving this zonal vulnerability in HIRI remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying pericentral HIRI in LT grafts.
• To identify key cellular crosstalk and molecular pathways contributing to zonal injury.

Main Methods:

• Integrated multi-omics approaches including single-cell and spatial transcriptomics, chromatin accessibility, proteomics, and bulk RNA-seq.
• Validation in clinical LT specimens, mouse HIRI models, and in vitro assays.
• Pharmacological inhibition of the identified SAA-driven pathway.

Main Results:

• HIRI disproportionately damages pericentral hepatocytes, correlating with increased macrophage crosstalk.
• Identified a FOXO1-driven SAA secretion from pericentral hepatocytes, recruiting and activating FPR2+ macrophages.
• This axis exacerbates pericentral hepatocyte injury and zonal disparities.
• Inhibition of SAA using Amilo-5MER reduced macrophage accumulation and mitigated pericentral damage.

Conclusions:

• The FOXO1/SAA/FPR2 axis is critical in mediating pericentral vulnerability during HIRI in LT.
• SAA represents a promising therapeutic target to reduce zonal injury and enhance liver graft outcomes post-transplantation.