Cardiac Macrophages Exhibit Dynamic Heterogeneity and Functional Specialization During Experimental Autoimmune...

Area of Science:

• Cardiovascular Research
• Immunology
• Single-cell Genomics

Background:

• Autoimmune myocarditis can lead to inflammatory cardiomyopathy due to complex immune and stromal cell interactions.
• Understanding the dynamic cellular communication is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the temporal and functional heterogeneity of cardiac macrophages and immune-stromal interactions during experimental autoimmune myocarditis (EAM).
• To identify key cellular players and communication pathways driving cardiac remodeling in EAM.

Main Methods:

• Single-nuclei RNA sequencing (snRNA-seq) was performed on cardiac nuclei from EAM mice at four distinct timepoints (day 0, 14, 21, 40).
• Cell-cell communication analysis and subclustering of macrophage populations were employed to dissect cellular interactions and functions.

Main Results:

• snRNA-seq identified 18 distinct cell populations, with a significant peak in intercellular signaling at day 14, dominated by fibroblasts and macrophages.
• Macrophage populations shifted from tissue-resident to recruited CCR2+ macrophages, exhibiting a pro-inflammatory signature and altered signaling pathways.
• Macrophage-fibroblast crosstalk was identified as a key driver of pro-inflammatory stromal activation.

Conclusions:

• The study delineates the dynamic heterogeneity of cardiac macrophages and highlights critical immune-stromal interactions in EAM progression.
• Findings suggest that targeting CCR2-mediated recruitment, SPP1 signaling, and macrophage-fibroblast crosstalk may offer precision therapeutic strategies for myocarditis.