Endothelial cells recruit pro-inflammatory macrophage clusters via App-Cd74 exacerbating ICI-associated myocarditis

Immune checkpoint inhibitor-related myocarditis (ICI-myocarditis) is a rare but highly threatening adverse reaction, and its pathogenesis is still unclear. Through single-cell RNA sequencing (scRNA-seq) of the heart tissues of the mouse ICI-myocarditis model, we identified a macrophage subset associated with the disease, which was defined by the co-expression of Cxcl9 and Cxcl10. This subset exhibited strong pro-inflammatory properties and activated a large number of pathways related to immune response and inflammatory reaction, including PI3K-AKT-MTOR-SIGNALING, IL2-STAT5-SIGNALING, MYC-TARGETS-V2, INFLAMMATORY-RESPONSE, IL6-JAK-STAT3-SIGNALING, etc. The analysis of intercellular communication indicated that endothelial cells were the main source of App, and they bound to Cxcl9⁺ Cxcl10⁺ Mac's Cd74, suggesting that the App-Cd74 signaling axis might become a potential therapeutic target for ICI-myocarditis. The deep learning framework scTenifoldXct verified the App-Cd74 axis as a significant ligand-receptor interaction. Our research provides a new perspective for in-depth understanding of the immune pathological mechanism of ICI-myocarditis and lays the foundation for the development of targeted therapeutic strategies.