Frontline Science: c‐Myc regulates P‐selectin glycoprotein ligand‐1 expression in monocytes during HIV‐1 infection. Issue 4 (1st October 2017) - Connor, Ryan
Abstract : The identification of c‐Myc as a potential PSGL‐1 transcriptional regulator facilitates the determination of the physiological significance of PSGL‐1 induction, and provides novel therapeutic targets. Abstract : Leukocyte extravasation is a crucial feature of the normal immune response to disease and infection and is implicated in various pathologies during chronic inflammatory disease. P‐Selectin glycoprotein ligand‐1 (PSGL‐1) is critical for leukocyte extravasation; however, despite extensive study, it remains unclear how its expression is regulated, which in turn, impedes a more precise understanding of how its expression level affects transmigration. To investigate the regulation of PSGL‐1, 60 subjects, with or without HIV infection, were recruited and PSGL‐1 expression in monocytes was measured. PSGL‐1 was found to be up‐regulated on leukocytes from HIV‐infected individuals, and the physiologically relevant mediators soluble CD40 ligand (sCD40L) and glutamate were able to induce PSGL‐1 transcription in human monocytes ex vivo. HIV‐1 induced PSGL‐1 induction, and its dependence on CD40L was validated further by use of the mouse‐tropic HIV (EcoHIV) mouse model of HIV infection in C57BL/6 and CD40L knockout (KO) mice. To investigate crosstalk between the signaling cascades induced by CD40L and glutamate that lead to PSGL‐1 induction, a network‐based, discrete dynamic model was developed. The model reveals the MAPK pathway and oxidative stress as critical mediators of crosstalk between CD40L and glutamate‐induced pathways. Importantly, the model predicted induction of the c‐Myc transcription factor upon cotreatment, which was validated using transcriptomic data and pharmacologic inhibition of c‐Myc. This study suggests a novel systems serology approach for translational research and reveals a mechanism for PSGL‐1 transcriptional regulation, which might be leveraged to identify novel targets for therapeutic intervention.