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

Author:

Krmeská Veronika1ORCID,Aggio Juliana Bernardi12ORCID,Nylén Susanne1,Wowk Pryscilla Fanini12ORCID,Rothfuchs Antonio Gigliotti1ORCID

Affiliation:

1. *Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; and

2. †Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, Brazil

Abstract

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.

Funder

Vetenskapsrådet

Karolinska Institutet

Sigurd och Elsa Goljes Minne

Instituto Carlos Chagas, Fundação Oswaldo Cruz

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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