IL-17 Induced Stromal Cell–Derived Factor-1 and Profibrotic Factor in Keloid-Derived Skin Fibroblasts via the STAT3 Pathway

Abstract

The pathogenesis of keloids has not been elucidated, and the disease is thought to be caused by abnormal secretion of proinflammatory mediators and irregular responses to other inflammatory signals mediated by keloid fibroblasts (KFs). In this study, we investigated whether a local increase in interleukin IL-17 in keloid tissues stimulates the production of stromal cell–derived factor-1 (SDF-1) in KFs causing further recruitment of IL-17-producing T helper 17 (Th17) cells, which subsequently creates a positive feedback loop. Histological assessment was performed and the change in the expression of IL-17, IL-1β, IL-6, and TNF-α which of fibrosis and inflammation associated markers was examined. In addition, fibroblasts were treated with IL-17 in the presence or absence of STAT3 inhibitor STA-21; SDF-1 levels and fibrosis genes were measured. Our results showed that fibrotic reaction and expression of proinflammatory cytokines including IL-17 were most prominent in the growing margin (perilesional area) of keloid tissue and Th17 cells significantly infiltrated the perilesional area. In addition, IL-17 upregulated the expression of SDF-1, collagen, and α-SMA in KFs. Finally, STA-21 decreased SDF-1α expression and the expression of fibrosis genes in KFs even after IL-17 stimulation. Our study demonstrated that a local increase in IL-17 in keloid tissues stimulates the production of SDF-1 in KFs causing further recruitment of IL-17-producing T helper 17 (Th17) cells, which subsequently creates a positive feedback loop. These findings suggest that STAT3 inhibition can be used to treat keloid scars by reversing the vicious cycle between Th17 cells and KFs.

RNA Sequencing Keloid Transcriptome Associates Keloids With Th2, Th1, Th17/Th22, and JAK3-Skewing

“…PI3, CCL20, S100As) axes, as well as the JAK/STAT signaling molecule JAK3. The up-regulation of Th17 markers expands upon prior reports demonstrating a role of Th17 mediators in keloids (11,55). Additionally, our results suggest that, similar to other fibrotic diseases (56), the Th1 axis is also involved to keloid pathogenesis.…”

“…Our group recently examined a few Th2 markers in keloids (20), while another study found increases for the IL-17/IL-22-induced products, S100A7 and hBD2 (53). Additionally, dysregulation of the IL-17/IL-6 axis (11) and/or JAK/STAT-signaling (54,55) have also been investigated. The present study expands on prior investigations and provides a comprehensive molecular profiling of keloids, identifying a significant immune component in both lesional and non-lesional skin, as well as linking keloids with fibrosis and cartilage/bone-differentiation.…”

“…AD, psoriasis, alopecia areata) (81), modulating a range of immune responses, including the Th2 (IL-4, IL-13, CCL18), Th1 (IFNg), and Th17/Th22 (CCL20, S100As) pathways (82). Preliminary studies evaluating inhibition of JAK/STAT signaling in human keloid fibroblasts (54,55), and in a humanized keloid animal model (83), have demonstrated promising results. There are several JAK inhibitors in clinical development showing efficacy for various dermatologic disorders (81,82,84) and could be a therapeutic strategy worth investigating in keloids.…”

Conditioned medium-preconditioned EPCs enhanced the ability in oligovascular repair in cerebral ischemia neonatal rats

“…In this work, we also conducted an iTRAQbased quantitative proteomic analysis, and the data reveals that 295 proteins were downregulated and 305 proteins were upregulated in OGD-ECs compared to normal control ECs (data not shown). It was known that several factors such as IL-17, HIF-1α, E2, and FGF-2 could regulate the expression of CXCL12 [36][37][38][39], and we are performing an in-depth study for the mechanisms of CXCL12 increase in EPCs in another study. EPCs-CM or EPC transplantation improves the white matter integrity, decreases capillary breakdown, and inhibits apoptosis after traumatic brain injury (TBI) [12,40].…”

Adiponectin, but Not TGF-β1, CTGF, IL-6 or TNF-α, May Be a Potential Anti-Inflammation and Anti-Fibrosis Factor in Keloid

“…Specimens were obtained from ten patients (5 males and 5 females, aged 25–48 years) with keloid and the adjacent normal skin tissues, cell cultures were established as described previously. 9 Briefly, the isolated skin specimen was placed in sterile petri dishes and washed with phosphate-buffered saline (PBS), then incubated with 2.5 mg/mL dispase II (Hoffman-La Roche, Indianapolis, IN, USA) overnight at 4°C. On the second day, the specimen was removed from the epidermis and subcutaneous tissues, and the dermis was manually cut as much as possible and then seeded in 6-well plates.…”