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

Sepsis-induced cardiomyopathy (SCM) is a life-threatening complication with poorly understood immune-metabolic drivers. This study aims to uncover the role of autophagy-dependent monocyte reprogramming and its contribution to myocardial injury via CCL7-mediated immune activation in sepsis.

We performed integrated analysis of bulk and single-cell transcriptomic data from septic patients (GSE65682, GSE152363, GSE167363). Autophagy activity and chemokine signaling were evaluated using bioinformatic approaches including WGCNA, pseudotime trajectory inference, and CellChat communication analysis. Functional validation was conducted through in vitro co-culture systems and in vivo models of LPS-induced sepsis, utilizing CCL7 neutralization, flow cytometry, ELISA, and Western blot.

Single-cell RNA sequencing revealed a distinct C6 monocyte subset characterized by high autophagic flux, elevated CCL7 expression, and an M1-like inflammatory phenotype. Pseudotime analysis positioned C6 monocytes at the terminal end of monocyte differentiation, where they functioned as chemokine hubs amplifying cross-talk with CD8+ T cells, NK cells, and neutrophils. Mechanistically, CCL7 secretion by C6 monocytes promoted autocrine M1 polarization and enhanced CD8+ T cell activation via CCR1/CCR2-dependent PI3K-AKT signaling. In co-culture, CCL7-stimulated CD8+ T cells induced oxidative stress, cytokine release, and cardiomyocyte apoptosis. In vivo, CCL7 neutralization alleviated myocardial injury, reduced cardiac ROS accumulation, and suppressed systemic inflammation.

Our findings identify a pathogenic autophagy-CCL7-monocyte-T cell axis as a central driver of immuno-metabolic dysregulation in SCM. Targeting CCL7-mediated signaling may represent a novel immunomodulatory strategy to restore cardiac immune homeostasis and mitigate sepsis-induced myocardial injury.