Targeting SELPLG/P‐selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter

Abstract

We previously identified a missense single nucleotide polymorphism rs2228315 (G>A, Met62Ile) in the selectin-P-ligand gene (SELPLG), encoding P-selectin glycoprotein ligand 1 (PSGL-1), to be associated with increased susceptibility to acute respiratory distress syndrome (ARDS). These earlier studies demonstrated that SELPLG lung tissue expression was increased in mice exposed to lipopolysaccharide (LPS)-and ventilator-induced lung injury (VILI) suggesting that inflammatory and epigenetic factors regulate SELPLG promoter activity and transcription. In this report, we used a novel recombinant tandem PSGL1 immunoglobulin fusion molecule (TSGL-Ig), a competitive inhibitor of PSGL1/P-selectin interactions, to demonstrate significant TSGL-Ig-mediated decreases in SELPLG lung tissue expression as well as highly significant protection from LPS-and VILI-induced lung injury.In vitro studies examined the effects of key ARDS stimuli (LPS, 18% cyclic stretch to simulate VILI) on SELPLG promoter activity and showed LPSmediated increases in SELPLG promoter activity and identified putative promoter regions associated with increased SELPLG expression. SELPLG promoter activity was strongly regulated by the key hypoxia-inducible transcription factors, HIF-1α, and HIF-2α as well as NRF2. Finally, the transcriptional regulation of SELPLG promoter by ARDS stimuli and the effect of DNA methylation on SELPLG expression in endothelial cell was confirmed.These findings indicate SELPLG transcriptional regulation by clinicallyrelevant inflammatory factors with the significant TSGL-Ig-mediated attenuation of LPS and VILI highly consistent with PSGL1/P-selectin as therapeutic targets in ARDS.

PSGL-1: a novel immune checkpoint driving T-cell dysfunction in obstructive sleep apnea

“…The hypoxemia is one of the main intermediate mechanisms of OSA. In this regard, a recent study reported that PSGL-1 expression increased susceptibility in patients with acute respiratory distress syndrome, demonstrating the PSGL-1 promoter activity was strongly regulated by HIF-1α and HIF-2α ( 39 ). Remarkably, hypoxia develops in most solid tumors because of the rapid growth of the tumor that outstrips the oxygen supply, and is one of the main hallmarks of tumor microenvironment ( 40 ).…”

“…Nevertheless, additional studies are needed to understand the implications of PSGL-1 axis in the context of OSA-related tumor initiation. On the other side, Sun et al., suggest that additional inflammatory and epigenetic factors may regulate PSGL-1 expression ( 39 ). Moreover, previous studies indicate an upregulation of PSGL-1 in acute inflammation ( 41 ).…”

A Razor's Edge: Vascular Responses to Acute Inflammatory Lung Injury/Acute Respiratory Distress Syndrome

“…Genome-wide association studies (GWAS) in Blacks with ARDS identified a coding SNP that influences the activity of the SELPLG-encoded PSGL1 (119). Similar to MYLK, CTTN, and NAMPT, ARDS stimuli increase SELPLG promoter activity via the participation of transcription factors that include HIF-1α/HIF-2α and NRF2 (120).…”

“…PSGL1 is an attractive ARDS target with several approaches to PSGL1 neutralization that have all attenuated lung injury in preclinical ARDS/VILI models. These include the FDA-approved P-selectin-binding humanized mAb, crizanlizumab (119,145), the human anti-PSGL1 mAb (CD162) (119), and TSGL-Ig, a novel recombinant tandem PSGL1 immunoglobulin fusion molecule (120).…”

Bioinformatics analyses of NET-related hub genes in chronic obstructive pulmonary disease and their association with immune infiltration

“…The therapeutic targeting of SELPLG and its encoded protein, PSGL-1, holds promise in substantially mitigating the severity of in ammatory lung injury, including respiratory distress syndrome (ARDS) and VILI. (Sun et al, 2023) Owing to these ndings, we hypothesized that MAPK1, PIK3CA, and SELPLG may be involved in the onset and progression of COPD via the establishment of NETs that trigger in ammation. Dectin-2 (CLEC6A) has been demonstrated to be correlated to dust mite-induced chronic airway in ammation.…”