Propagation of monocyte exhaustion memory and underlying mechanisms.

Summary

Using co-culture models, the authors show that LPS-induced exhausted monocytes transmit an exhaustion phenotype to naïve monocytes, induce endothelial apoptosis and adhesion molecule upregulation, and suppress T-cell proliferation. CD38 inhibition mitigates these effects, and mTOR signaling is implicated as a key regulator, positioning the CD38–mTOR axis as a therapeutic target in sepsis-related immune dysfunction.

Key Findings

• Exhausted monocytes induced by prolonged LPS propagate exhaustion to neighboring naïve monocytes.
• Exhausted monocytes trigger endothelial apoptosis, upregulate ICAM-1/VCAM-1, and enhance monocyte transmigration.
• CD38 inhibition mitigates endothelial injury and restores T-cell proliferation and activation.
• mTOR signaling regulates exhaustion propagation; its inhibition downregulates exhaustion markers and STAT1/STAT3/S6K signaling.

Clinical Implications

Targeting CD38 or mTOR could help reverse immunosuppression and vascular barrier injury in sepsis. While clinical translation requires in vivo validation, these pathways inform drug repurposing (e.g., CD38/mTOR inhibitors) and biomarker development.

Limitations

• In vitro models without in vivo validation limit generalizability to human sepsis.
• LPS-induced exhaustion may not fully recapitulate clinical pathogen- and host-driven heterogeneity.

Future Directions

Validate CD38–mTOR targeting in in vivo sepsis models and assess translational biomarkers of monocyte exhaustion and endothelial injury in patients.