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.