Autophagy-driven CCL7+ monocyte terminal differentiation program fuels CD8+ T cell-mediated cardiac injury in Sepsis.

Summary

Single-cell and bulk transcriptomics identified a terminally differentiated, autophagy-high, CCL7+ monocyte subset that functions as a chemokine hub to activate CD8+ T cells via CCR1/CCR2–PI3K–AKT signaling, driving myocardial injury in sepsis. In vivo CCL7 neutralization mitigated cardiac injury, oxidative stress, and systemic inflammation, nominating CCL7 signaling as a therapeutic target for sepsis-induced cardiomyopathy.

Key Findings

• A C6 monocyte subset with high autophagy and CCL7 expression was positioned at the terminal end of monocyte differentiation and acted as a chemokine hub.
• CCL7 promoted autocrine M1 polarization and enhanced CD8+ T cell activation via CCR1/CCR2-dependent PI3K–AKT signaling.
• In vivo CCL7 neutralization reduced myocardial injury, cardiac ROS, and systemic inflammation in LPS-induced sepsis.

Clinical Implications

CCL7/CCR1/CCR2 pathway inhibitors could be explored to mitigate sepsis-induced cardiomyopathy. The identified CCL7+ monocyte phenotype may serve as a biomarker to stratify risk and monitor response in immunomodulatory trials.

Limitations

• Use of LPS-induced sepsis model may not capture full heterogeneity of human sepsis
• Absence of clinical interventional data and unclear patient sample sizes across datasets

Future Directions

Evaluate CCL7/CCR2 blockade in polymicrobial sepsis (e.g., CLP) and conduct early-phase trials in sepsis-induced cardiomyopathy; develop assays to quantify CCL7+ monocyte signatures for patient selection.