Converse regulation of CCR7-driven human dendritic cell migration by prostaglandin E₂ and liver X receptor activation

Abstract

Migration and homing of DCs to lymphoid organs is pivotal for inducing adaptive immunity and tolerance. DC homing depends on the chemokine receptor CCR7. However, expression of CCR7 alone is not sufficient for effective DC migration. A second signal, mediated by prostaglandin E2 (PGE2), is critical for the development of a migratory DC phenotype. PGE2 is important for inducing efficient immune responses, but, if deregulated, contributes to chronic inflammation, autoimmune diseases through Th17-cell development and tumorigenesis. In contrast, activation of liver X receptor (LXR)α has recently been shown to interfere with CCR7 expression and migration of DCs resulting in a reduced immune response. Here, we demonstrate that PGE2 downregulates LXRα expression in human monocyte derived as well as ex vivo DCs. Moreover, PGE2 stimulation dampens LXR activation, auto-regulation and LXR-mediated gene transcription. Consequently, we show that PGE2 enhances CCR7 expression and migration of LXR-activated DCs. Furthermore, we provide evidence that PGE2 signaling and LXR activation specifically elicit converse effects on CCR7 expression and DC migration. In contrast, production of MMP9, CCL4, COX-2, and IL-23 is solely regulated by PGE2, but not by LXR activation, offering new perspectives for therapeutic interventions.