Abstract
Aberrant polymorphonuclear neutrophil (PMN) accumulation in tissues induces chronic vascular diseases. Endothelial cells (ECs) regulate the access of PMNs into the tissue from the blood. However, the mechanisms that prevent PMNs from being activated and accumulating in the tissue, a hallmark of acute lung injury (ALI), remain elusive. We demonstrate that conditional deletion of Erg in ECs spontaneously alters the PMN transcriptome, which is enriched with genes that induce PMN recruitment, adhesion, activation, and “do not eat me” signals due to impaired synthesis of the deubiquitinase A20. Decreased A20 levels, in turn, activated the transcription factor NF-κB and the secretion of MIP2α (human homolog of IL-8) in ECs. EC-secreted MIP2α/IL-8 engaged the CXCR2 cascade on PMNs, leading to their activation and inflammatory injury. These findings were recapitulated in the lungs and blood of PMNs from patients dying of ALI. Overexpression of the A20 gene in ECs or pharmacological inhibition of CXCR2 on PMNs in iEC-Erg–/– mice rescued EC control of PMNs and tissue homeostasis, and enhanced mouse survival after pneumonia. Thus, the EC/Erg/A20 axis regulates PMN accumulation and hyperactivation in the lungs by inhibiting EC-mediated IL-8 activation of PMN CXCR2, thereby providing a potential target for neutrophilic inflammatory vascular diseases.
Authors
Vigneshwaran Vellingiri, Vijay Avin Balaji Ragunathrao, Jagdish Chandra Joshi, Md Zahid Akhter, Mumtaz Anwar, Somenath Banerjee, Sayanti Datta, Viktor Pinneker, Steven Dudek, Yoshikazu Tsukasaki, Sandra Pinho, Dolly Mehta
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