Abstract
AbstractThe initiation of immune responses is associated with the maturation of dendritic cells (DCs) and their migration to draining lymph nodes. En route activated DCs encounter cells of the tissue microenvironment, such as fibroblasts. Because we have shown that DCs interact with fibroblasts during immune responses, we studied the impact of skin fibroblasts on human monocyte-derived DC function and subsequent human T-cell (TC) differentiation. We show that fibroblasts support interleukin-23 (IL-23) secretion from DCs preactivated by lipopolysaccharide (DCact) compared with lipopolysaccharide-activated DCs alone. The underlying complex feedback-loop mechanism involves IL-1β/tumor necrosis factor-α (from DCact), which stimulate fibroblasts prostaglandin E2 production. Prostaglandin E2, in turn, acts on DCact and increases their IL-23 release. Furthermore, fibroblast-stimulated DCact are far superior to DCact alone, in promoting the expansion of Th17 cells in a Cox-2-, IL-23-dependent manner. Using CD4+CD45RO+ memory TCs and CD4+CD45RA+ naive TCs, we showed that fibroblasts induce a phenotype of DCact that promotes the expansion of Th17 cells. Moreover, in psoriasis, a prototypic immune response in which the importance of IL-23/Th17 is known, high expression of Cox-2 in fibroblasts was observed. In conclusion, skin fibroblasts are involved in regulation of IL-23 production in DCs and, as a result, of Th17 expansion.
Highlights
Dendritic cells (DCs) are in permanent contact with their tissue microenvironment
Monocyte-derived DCs were preactivated with LPS (DCact) for 3 hours to imitate DCs within an inflammatory environment
DCact were cocultured with skin-derived fibroblasts, and IL-23 was measured in the coculture supernatants
Summary
Dendritic cells (DCs) are in permanent contact with their tissue microenvironment. For example, niches created by the stromal microenvironment in the bone marrow enable DC precursors to differentiate into DC subpopulations.[1,2] In peripheral tissues, DCs interact with a microenvironment composed of the extracellular matrix and stromal cells, such as fibroblasts, macrophages, and endothelial cells. 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. Zhang et al reported splenic stromal cells to drive DCs toward a regulatory phenotype.[8] emigration of Langerhans cells from the skin to the lymph node is influenced by a lack of matrix-associated SPARC (secreted protein, acidic and rich in cysteine), resulting in enhanced cutaneous contact hypersensitivity.[9]. We show that skin fibroblasts actively participate in the regulation of an immune response by affecting the IL-23 production of DCs and supporting the Th17 cell expansion
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