Dermal Fibroblasts Promote the Migration of Dendritic Cells

Abstract

Migration of dendritic cells (DCs) from skin to lymph nodes on activation is an essential step in the initiation of an adequate immune response. The dermal microenvironment including stromal cells and their soluble factors might be involved in the regulation of DC migration. To focus on the role of dermal fibroblasts, we studied whether interaction of DCs with fibroblasts promotes the migration of DCs. DCs were co-cultured with resting fibroblasts or with tumor necrosis factor (TNF)alpha/IL-1beta-activated fibroblasts to mimic an inflammatory microenvironment. Interaction of DCs with TNFalpha/IL-1beta-stimulated fibroblasts increased the secretion of matrix metalloproteinase-9 (MMP-9) from DCs within 6 hours compared with DCs alone or DCs stimulated with lipopolysaccharide or TNFalpha/IL-1beta. In contrast, unstimulated fibroblasts did not affect MMP-9 secretion. IL-6 released by TNFalpha/IL-1beta-stimulated fibroblasts was identified as a factor responsible for fibroblast-stimulated MMP-9 secretion from DCs. In accordance with the elevated MMP-9 release, on co-culture with TNFalpha/IL-1beta-stimulated fibroblasts, DCs migrated significantly more effectively through matrigel matrices than did TNFalpha/IL-1beta-stimulated DCs. This was inhibited by a selective blocking of MMP-9, indicating the importance of MMP-9 for this migratory capacity of DCs. In summary, fibroblasts in the local dermal microenvironment are capable of potentiating the migratory capacity of DCs, and thus have the potential to actively participate in the regulation of a cutaneous immune response.

Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8–mediated activation of TGF-β

“…Cytokines are released by fibroblasts in patterns that distinguish fibroblasts from different anatomic sites and disease states (33,34,60). These studies validate and extend recent in vitro studies suggesting that cultured skin fibroblasts stimulated with TNF/IL-1 can promote DC migration or increase the maturation of LPS-stimulated DCs by a complex feedback mechanism involving IL-1β secreted from DCs (62,63). Our data now demonstrate that in physiologic models, fibroblast Itgb8 is required for lung DC migration.…”

Human fibroblasts support the expansion of IL-17–producing T cells via up-regulation of IL-23 production by dendritic cells

“…3 Morphologic analysis and high expression of CD1a and CD11c were parameters for quality and purity of DC preparations. An immature phenotype of DCs was verified by low expression of CD80, CD83, CD86, and HLA-DR.…”

“…Recently, we demonstrated an interaction of DCs and fibroblasts, resulting in enhanced migration of DCs. 3 Several groups reported the effect of stromal cells on the regulation of DC functions under steady-state as well as inflammatory conditions. 4,5 Renkl et al 6 and Termeer et al 7 showed that maturation and differentiation of DCs are regulated by the extracellular matrix components hyaluronic acid and osteopontin.…”

Human Cytomegalovirus-Encoded Human Interleukin-10 (IL-10) Homolog Amplifies Its Immunomodulatory Potential by Upregulating Human IL-10 in Monocytes

“…We also examined primary human foreskin fibroblasts (HFFs), which is a cell type permissive to productive HCMV replication that has also been shown to play an important role in regulating a variety of immune functions (26)(27)(28). In three independent replicate experiments, both MDMs and MDDCs significantly upregulated hIL-10 in response to cmvIL-10 treatment, whereas hIL-10 remained below detectable limits before and after cmvIL-10 treatment of CD4 ϩ and CD8 ϩ T cells and HFFs.…”