Single-cell profiling identifies an AIM2-dependent macrophage program amplifying T cell-mediated acute cardiac...

Area of Science:

• Immunology
• Transplantation Biology
• Molecular Medicine

Background:

• Cardiac allograft rejection involves complex immune responses, including macrophage infiltration and activation.
• Understanding macrophage heterogeneity and specific activation pathways is crucial for developing targeted therapies.
• The role of inflammasomes, particularly AIM2, in transplant rejection remains incompletely understood.

Purpose of the Study:

• To characterize macrophage subsets in cardiac grafts using single-cell RNA sequencing.
• To investigate the activation of the AIM2 inflammasome pathway in pro-inflammatory macrophages during rejection.
• To assess the therapeutic potential of AIM2 inhibition in mitigating cardiac allograft rejection.

Main Methods:

• Analysis of murine heart transplant scRNA-seq datasets to define macrophage subsets.
• Integration of human endomyocardial biopsy transcriptomic data with macrophage RNA-seq.
• In vitro and in vivo validation of findings, including AIM2 inhibition experiments.

Main Results:

• scRNA-seq identified an expansion of M1-like macrophages with upregulated AIM2 inflammasome components in rejecting grafts.
• Human biopsies showed increased M1 macrophages and enhanced AIM2 activity correlating with rejection severity.
• AIM2 inhibition reduced macrophage costimulatory molecule expression, T cell proliferation, and improved murine cardiac graft survival.

Conclusions:

• An IFN-driven AIM2 axis in M1-like macrophages amplifies T cell-mediated acute cardiac allograft rejection.
• Targeting AIM2 attenuates macrophage activation and T cell priming, mitigating rejection.
• AIM2 inhibition represents a promising adjunct strategy for improving heart transplant outcomes.