Cyclooxygenase-Derived Prostaglandin E₂ Drives IL-1-Independent Mycobacterium bovis Bacille Calmette-Guérin-Triggered...

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.