Abstract
Fibroblasts play an important role as members of the innate immune system through the secretion of COX-2-derived inflammatory mediators such as prostaglandin E2 (PGE2). However, it has been described that dermal fibroblasts behave like mesenchymal stem cells reducing lymphocyte recruitment and dendritic cell activation through PGE2 release. As the role of fibroblasts in psoriasis remains poorly characterized, in the present study we have evaluated the possible influence of PGE2 derived from dermal fibroblasts as modulator of the immune response in psoriatic skin. Our results indicate that under inflammatory conditions, psoriatic fibroblasts showed defective induction of COX-2, which resulted in diminished production of PGE2, in contrast to healthy fibroblasts. This phenotype correlated with deficient c-Jun N-terminal kinase (JNK) activation, in accordance with the hypothesis that alterations in members of the JNK pathway are associated with psoriasis. Furthermore, conditioned medium from psoriatic fibroblasts promoted the polarization of monocytic cells toward a pro-inflammatory profile, effect that was mimicked in healthy fibroblasts after pre-incubation with indomethacin. These results are consistent with a prominent role of dermal fibroblasts in the regulation of inflammatory response through the participation of COX-derived metabolites. This resolutive behavior seems to be defective in psoriatic fibroblasts, offering a possible explanation for the chronification of the disease and for the exacerbation triggered by nonsteroidal anti-inflammatory drugs (NSAIDS) such as indomethacin.
Highlights
Psoriasis is a chronic skin inflammatory disease characterized by the appearance of scaly plaques as result of the interplay of genetic, environmental, and immunological factors [1, 2]
Several studies using fibroblasts obtained from surgical resections of healthy skin suggest that prostaglandin E2 (PGE2) may contribute to psoriasis pathogenesis by promoting recruitment and activation of Tcells, dendritic cells and monocytes [14, 15]
Recent studies suggest that tissue-resident stromal cells such as fibroblasts are critically positioned at the cellular and molecular basis for disease persistence, as regulators of the switch from acute resolving to chronic persistent inflammation [5]
Summary
Psoriasis is a chronic skin inflammatory disease characterized by the appearance of scaly plaques as result of the interplay of genetic, environmental, and immunological factors [1, 2]. Fibroblasts are stromal cells, responsible for the synthesis and remodeling of extracellular matrix components, which regulate homeostasis and play a critical role during tissue development, differentiation, and repair [5] They are considered members of the innate immune system and could contribute to the pathogenesis of several diseases, such as rheumatoid arthritis or tumor development, through the secretion of cytokines, chemokines, or eicosanoids [6,7,8]. Synovial fibroblasts develop a direct inflammatory phenotype in the inflamed synovium, whereas dermal fibroblasts are more functionally similar to mesenchymal stem cells, limiting cytokine sensitivity of vascular endothelium, lymphocyte recruitment and dendritic cell activation [5, 9, 10]. These regulatory effects are in part mediated by classically considered pro-inflammatory mediators such as prostaglandin E2 (PGE2), which is highly produced by healthy dermal fibroblasts [11, 12]
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