Session Type: Abstract Submissions (ACR)
Systemic sclerosis (SSc) is a severe disease of unknown aetiology characterised by cellular injury and activation in early stage, followed by autoimmunity and fibrosis. Much of the work is focused on the fibroblasts however, keratinocytes are known to be able to secrete chemo-attracting agents, as well as growth factors influencing phenotype and proliferation rate of fibroblasts. We have recently shown that SSc epithelial cells exhibit an activated phenotype similar to wound healing. Data from hypertrophic scaring and keloids demonstrate that epidermis can promote dermal fibrosis. Therefore, we decided to look for evidence that in SSc injured epidermal cells are releasing chemokines and cytokines capable of recruiting immune cells to the skin and promoting fibrosis.
Forearm biopsies were taken from 12 healthy controls and 12 SSc patients. Dermis and epidermis were separated using trypsin/EDTA and the explants incubated overnight in serum free media. The conditioned media were then collected and analysed using Legend PLEX (BioLegend) for presence of G-CSF, GM-CSF, VEGF, PDGF-AA, PDGF-BB, MCP-1, FGF-2, IL-8, IL-6, IL-1α, IL-1β, and IL-1ra. Additionally, HGF, CCL20 and S100A9 were measure by ELISA (R&D Systems). Moreover, immunohistochemistry was performed on skin biopsies of 6 dcSSc and 6 healthy controls using antibodies against S100A9, S100A8, loricrin and involucrin. The epidermal thickness and cell area were also measured. The statistical analysis was performed using Wilcoxon rank-sum test.
The conditioned media analysis revealed significantly higher levels of HGF (p<0.005) and S100A9 (p< 0.05) released by SSc epidermis. Also increased levels of FGF-2, VEGF-A and PDGF-AA and IL-8 found in the SSc epidermis conditioned media showed a trend towards significance. Staining of skin sections confirmed much higher levels of S100A9 in SSc present throughout the epidermis, compared to positive staining in the healthy skin only around epidermal appendages. The SSc epidermis showed significant increase in thickness (p<0.05) and hypertrophic cells in basal (p<0.005) and spinous layers (p<0.005). The expression of involucrin and loricrin was also altered.
The epidermis provides a potential source of chemokines in SSc. High levels of pro-inflammatory S100A9 released by SSc dermis might contribute to the inflammation and therefore skin fibrosis. The abnormal thickness, hypertrophic keratinocytes and altered expression of differentiation markers in SSc epidermis suggest changes in terminal differentiation and signalling. The increase in HGF release by SSc epidermis is consistent with our previous report of enhanced c-Met activation in SSc epidermis and, indicates autocrine stimulation that could be responsible for the changes observed. However, more investigations are required to fully explore the mechanisms underlying S100A9 and c-Met/HGF signaling and they role of in skin fibrosis.
J. Nikitorowicz Buniak,
C. P. Denton,
D. J. Abraham,
R. J. Stratton,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhanced-release-of-s100a9-and-hepatocyte-growth-factor-by-the-epidermis-in-systemic-sclerosis/