Endothelial-Derived CCL7 Promotes Macrophage Polarization and Aggravates Septic Acute Lung Injury via CCR1-Mediated STAT1 Succinylation.
Summary
Endothelial CCL7 drives CCR1+ macrophage metabolic reprogramming and M1 polarization via KAT2A-dependent STAT1 succinylation, amplifying inflammation in septic ALI. Endothelial-specific CCL7 inhibition reduced lung injury severity in sepsis models, nominating the CCL7–CCR1–KAT2A–STAT1 axis as a therapeutic target.
Key Findings
- Endothelial cells secrete CCL7 that induces metabolic reprogramming and M1 polarization of CCR1+ macrophages.
- Endothelial-specific inhibition of CCL7 reduces the severity of septic acute lung injury in vivo.
- CCL7–CCR1 signaling increases KAT2A expression, enhancing STAT1 succinylation and binding to promoters of glycolytic genes to drive inflammatory cascades.
Clinical Implications
CCR1 antagonists or strategies to modulate endothelial CCL7 release and STAT1 succinylation could attenuate inflammatory lung injury in sepsis, informing target selection for translational studies.
Why It Matters
This study reveals an epigenetic-metabolic mechanism linking endothelial chemokine signaling to macrophage polarization and lung injury, identifying druggable nodes (CCR1, KAT2A, STAT1 succinylation).
Limitations
- Preclinical murine models without human clinical validation
- Abstract truncation limits details on knockout phenotypes and breadth of experimental systems
Future Directions
Test CCR1 antagonists or KAT2A/STAT1-succinylation modulators in sepsis ALI models and evaluate endothelial CCL7/CCR1 signatures in human cohorts to enable biomarker-guided trials.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic study in animal models and cells
- Study Design
- OTHER