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

Vellingiri, V.; Avin BR, V.; Joshi, J. C.; Akhter, M. Z.; Anwar, M.; Banerjee, S.; Dudek, S.; Tsukasaki, Y.; Pinho, S.; Mehta, D.

doi:10.1101/2024.05.02.591799

bioRxiv · 10.1101/2024.05.02.591799

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

Vellingiri, V.·Avin BR, V.·Joshi, J. C.·Akhter, M. Z.·Anwar, M.·Banerjee, S.·Dudek, S.·Tsukasaki, Y.·Pinho, S.·Mehta, D.

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Abstract

Neutrophils (PMNs) reside as a marginated pool within the vasculature, ready for deployment during infection. However, how endothelial cells (ECs) control PMN extravasation and activation to strengthen tissue homeostasis remains ill-defined. Here, we found that the vascular ETS-related gene (ERG) is a generalized mechanism regulating PMN activity in preclinical tissue injury models and human patients. We show that ERG loss in ECs rewired PMN-transcriptome, enriched for genes associated with the CXCR2-CXCR4 signaling. Rewired PMNs compromise mice survival after pneumonia and induced lung vascular inflammatory injury following adoptive transfer into naive mice, indicating their longevity and inflammatory activity memory. Mechanistically, EC-ERG restricted PMN extravasation and activation by upregulating the deubiquitinase A20 and downregulating the NF{kappa}B-IL8 cascade. Rescuing A20 in EC-Erg-/- endothelium or suppressing PMN-CXCR2 signaling rescued EC control of PMN activation. Findings deepen our understanding of EC control of PMN-mediated inflammation, offering potential avenues for targeting various inflammatory diseases. HighlightsO_LIERG regulates trans-endothelial neutrophil (PMN) extravasation, retention, and activation C_LIO_LILoss of endothelial (EC) ERG rewires PMN-transcriptome C_LIO_LIAdopted transfer of rewired PMNs causes inflammation in a naive mouse C_LIO_LIERG transcribes A20 and suppresses CXCR2 function to inactivate PMNs C_LI In brief/blurbThe authors investigated how vascular endothelial cells (EC) control polymorphonuclear neutrophil (PMN) extravasation, retention, and activation to strengthen tissue homeostasis. They showed that EC-ERG controls PMN transcriptome into an anti-adhesive and anti-inflammatory lineage by synthesizing A20 and suppressing PMNs-CXCR2 signaling, defining EC-ERG as a target for preventing neutrophilic inflammatory injury.

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Vellingiri, V., Avin BR, V., Joshi, J. C., Akhter, M. Z., Anwar, M., Banerjee, S., Dudek, S., Tsukasaki, Y., Pinho, S., Mehta, D.. 2024-05-05. Endothelial ERG programs neutrophil transcriptome for sustained anti-inflammatory vascular niche. https://doi.org/10.1101/2024.05.02.591799

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