Endothelial ERG programs neutrophil transcriptome for sustained anti-inflammatory vascular niche

Area of Science:

• Vascular biology and immunology
• Endothelial cell (EC) and neutrophil (PMN) interactions
• Inflammation and tissue homeostasis

Background:

• Endothelial cells (ECs) play a critical role in regulating neutrophil (PMN) extravasation and activation, crucial for maintaining tissue homeostasis.
• The precise mechanisms by which ECs control PMN behavior, particularly their inflammatory memory, remain incompletely understood.

Approach:

• Investigated the role of vascular ETS-related gene (ERG) in ECs controlling PMN activity using preclinical models and human samples.
• Analyzed PMN transcriptome changes upon ERG loss in ECs, focusing on signaling pathways like CXCR2-CXCR4.
• Utilized adoptive transfer of 'rewired' PMNs to assess their inflammatory potential in naïve mice.
• Examined the molecular mechanisms involving A20, NFκB, and IL8 cascades regulated by EC-ERG.

Key Points:

• Endothelial ERG acts as a generalized regulator of PMN activity in tissue injury.
• Loss of ERG in ECs rewires PMN transcriptome, enhancing CXCR2-CXCR4 signaling and promoting inflammatory memory.
• Rewired PMNs exhibit increased longevity and inflammatory capacity, compromising host survival and causing vascular injury.
• EC-ERG upregulates A20 and downregulates the NFκB-IL8 cascade to restrict PMN extravasation and activation.

Conclusions:

• Endothelial ERG controls PMN behavior by inducing an anti-adhesive and anti-inflammatory phenotype through A20 synthesis and CXCR2 signaling suppression.
• Restoring A20 in ECs or inhibiting PMN-CXCR2 signaling can rescue EC control over PMN activation.
• Targeting EC-ERG presents a potential therapeutic strategy for mitigating neutrophilic inflammatory diseases.