Defective Induction of COX-2 Expression by Psoriatic Fibroblasts Promotes Pro-inflammatory Activation of Macrophages

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 E 2 (PGE 2 ). However, it has been described that dermal fibroblasts behave like mesenchymal stem cells reducing lymphocyte recruitment and dendritic cell activation through PGE 2 release. As the role of fibroblasts in psoriasis remains poorly characterized, in the present study we have evaluated the possible influence of PGE 2 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 PGE 2 , 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.

The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer

“…JNK inhibition with SP600125 reduced IL-1β-mediated COX-2 mRNA levels in normal fibroblasts, indicating that JNK is directly involved in the regulation of COX-2 expression. Together, these findings implicate that defective JNK function in fibroblasts contributes to psoriasis linked to deficient PGE2 function [77].…”

“…Conversely, CCL27, a cutaneous T-cell attracting chemokine, is found downregulated in lesional psoriatic skin via IL-17 and IFNγ partially through JNK regulation of cyclooxygenase-2 (COX-2) [76]. In healthy skin fibroblasts, COX-2 induces the production of prostaglandin E2 (PGE2), which then suppresses immunity by increasing the expression of IL-10 and reducing pro-inflammatory cytokines such as IL-23 and TNFα [77]. Fibroblasts derived from psoriatic plaques were found defective in JNK signaling and PGE2 production in response to IL-1β stimulation, both of which were correlated with reduced COX-2 expression.…”

Promoter Methylation Leads to Decreased ZFP36 Expression and Deregulated NLRP3 Inflammasome Activation in Psoriatic Fibroblasts

“…Regarding the cell model in which such possible psoriasis-TTP-inflammasome axis is verified, we decided to use fibroblasts relying on various inflammasome studies performed in this cell type, ranging from cardiac fibroblasts (32) to cancer-associated fibroblasts (33), oral mucosa, lung, and dermal fibroblasts (34)(35)(36). Moreover, published data (5,37,38) suggest that fibroblasts play an important role in the persistence and in the chronic inflammation state characterizing the disease. Our hypothesis is also strengthened by the fact that IL-1β has also been described as a direct target of TTP (39).…”

“…In this regard, early studies proposed that psoriatic fibroblasts could proliferate more than healthy fibroblasts ( 3 ); to date, such observation has not been definitively validated, while the attention shifted in turn from fibroblasts to keratinocytes ( 4 ). In more recent studies, fibroblasts are thought to rather play a role in maintaining the chronic inflammatory state of psoriatic skin and keratinocytes' proliferation ( 5 , 6 ). In this context, the observations reported in this work are in accordance with these latest articles.…”

Dermal Drivers of Injury-Induced Inflammation: Contribution of Adipocytes and Fibroblasts

“…These studies highlight the broad pro-inflammatory capacity of dermal fibroblasts. Interestingly, proteomic analysis of fibroblasts from psoriatic patients confirms higher levels of inflammation-associated proteins, such as TNFα [ 99 ] and supernatant from psoriatic fibroblasts induces an inflammatory macrophage phenotype [ 100 ]. Additionally, fibroblasts from atopic dermatitis patients induce inflammatory gene expression in cultured skin equivalents [ 101 ].…”