Fibroblasts support migration of monocyte-derived dendritic cells by secretion of PGE2 and MMP-1

The outcome of a cutaneous immune response is critically dependent upon the ability of dendritic cells (DC) to migrate from skin to the draining lymph nodes - a process that is influenced by the cutaneous tissue microenvironment. Here, the role of fibroblasts - a major component of the dermal microenvironment - on the migratory capacity of monocyte-derived DC (MoDC) was investigated in a 3D collagen I matrix. Indeed, dermal fibroblasts supported the migration of pre-activated MoDC through a 3D collagen I matrix. Activation of human MoDC resulted in the release of TNFα and IL-1β that in turn stimulated MMP-1 (human collagenase) and PGE2 secretion by human dermal fibroblasts. Transmigration assays confirmed the importance of fibroblast-derived MMP-1 and PGE2 for the migration of MoDC through a 3D collagen I matrix. Finally, in mice initiation of inflammation by induction of an irritant contact dermatitis or a psoriasis-like skin inflammation, the expression of the PGE2 generating cox-2 and the mouse collagen I degrading enzyme matrix metalloproteinases (MMP)-13 was strongly up-regulated. Our study indicates that MoDC are able to instruct dermal fibroblasts resulting in enhanced migratory capability of MoDC, thus highlighting the role of a crosstalk of DC with their stromal microenvironment for the control of cutaneous immune responses.