Frontline Science: c-Myc regulates P-selectin glycoprotein ligand-1 expression in monocytes during HIV-1 infection

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.

Editorial: Convergence of multiple pathways in PSGL-1 activation and leukocyte transmigration: therapeutic implications

“…By using the novel mouse-tropic HIV (EcoHIV) and C57BL/6 CD40L knockout mice, Connor et al demonstrated an increase in PSGL-1 gene expression during EcoHIV infection in wild-type mice that was not witnessed in CD40L knockout mice. Furthermore, pharmacologic inhibition of c-Myc demonstrated a role for this proto-oncogene in the induction of PSGL-1 transcription [2]. This work also identified the requirement for glutamate in addition to CD40L, likely functioning via an N-methyl-D-aspartate receptor-independent mechanism.…”

“…The mechanism of PSGL-1 gene activation by cytokines and transcription factors has been largely understudied until now. The article by Connor et al [2] that accompanies this editorial provides important mechanistic insights regarding PSGL-1 induction during HIV infection, where sCD40L and glutamate are both required mechanistically (Fig. 1).…”

“…NAC has been also demonstrated to inhibit HIV replication [4]. NAC is safely consumed as a nutritional supplement and is commonly used to treat oxidative stress caused by acetaminophen overdose by As Connor et al [2] mention in their discussion, to fully understand the role PSGL-1 plays in HIV infection, it is important to understand the mechanism by which glutamate is released. It has been proposed that glutamate can be released from cells via 6 known mechanisms: 1) glutamate can be released by the reversal of uptake by glutamate transporters; 2) opening of anion channels during cell swelling; 3) Ca 2+dependent exocytosis; 4) glutamate exchange via the cysteine-glutamate antiporter; 5) release via ionotropic purinergic receptors; and 6) unpaired hemichannels, such as pannexins from the cell surface [5].…”

“…On the basis of the findings by Connor et al and the discussion here, multiple approaches can be used to modulate PSGL-1-mediated inflammation via glutamate and CD40Lassociated pathways, with potential implications for therapeutic intervention in Figure 1. Graphic representation of the mechanism of action of CD40L and glutamate in PSGL-1 activation [2]. PSGL-1 transcription and gene expression is induced by glutamate and CD40L (middle).…”

Executable pathway analysis using ensemble discrete-state modeling for large-scale data

“…Discrete state network modeling facilitates prioritization of experiments by using simple logic rules such as ‘AND’ or ‘OR’ to explicitly define signal integration, enabling investigation of cross-talk and downstream events as shown in our previous studies. [4–6].…”