Cyclooxygenase-Derived Prostaglandin E2 Drives IL-1–Independent Mycobacterium bovis Bacille Calmette-Guérin–Triggered Skin Dendritic Cell Migration to Draining Lymph Node

Abstract

Inoculation of Mycobacterium bovis Bacille Calmette-Guérin (BCG) in the skin mobilizes local dendritic cells (DC) to the draining lymph node (dLN) in a process that remains incompletely understood. In this study, a mouse model of BCG skin infection was used to investigate mechanisms of skin DC migration to dLNs. We found enhanced transcription of cyclooxygenase (COX)-2 and production of COX-derived PGE2 early after BCG infection in skin. Animals treated with antagonists for COX or the PGE2 receptors EP2 and EP4 displayed a marked reduction in the entry of skin DCs and BCG to dLNs, uncovering an important contribution of COX-derived PGE2 in this migration process. In addition, live BCG bacilli were needed to invoke DC migration through this COX-PGE2 pathway. Having previously shown that IL-1R partially regulates BCG-induced relocation of skin DCs to dLNs, we investigated whether PGE2 release was under control of IL-1. Interestingly, IL-1R ligands IL-1α/β were not required for early transcription of COX-2 or production of PGE2 in BCG-infected skin, suggesting that the DC migration-promoting role of PGE2 is independent of IL-1α/β in our model. In DC adoptive transfer experiments, EP2/EP4, but not IL-1R, was needed on the moving DCs for full-fledged migration, supporting different modes of action for PGE2 and IL-1α/β. In summary, our data highlight an important role for PGE2 in guiding DCs to dLNs in an IL-1–independent manner. Key Points BCG-triggered PGE2 release mobilizes skin DCs to the draining lymph node. Migrating DCs use EP2 and EP4 to relocate to the draining lymph node. Live BCG bacilli are needed for PGE2-mediated DC migration.