LB813 Palmitoyl-KVK-L-ascorbic acid increases type I procollagen expression by inhibition of DNA methyltrasferase activity

Abstract

Morphea is a disease of dermal inflammation and resultant sclerosis with considerable functional and cosmetic consequences. Cellular and molecular events in pathogenesis of morphea remain poorly elucidated. Preliminary studies using genome-wide gene expression analysis support the role of gamma interferon mediated pathways in the early pathogenesis of morphea. Specifically, CXCL-9 and 10, known ligands of CXCR3 receptor, were shown to be strongly upregulated in morphea. The purpose of this study is to characterize the inflammatory infiltrate in morphea and investigate cell-type specific expression of CXCR3 ligands in morphea using immunohistochemistry (IHC). Our data show that the cellular infiltrate of early inflammatory morphea lesions consists of predominantly T lymphocytes, with significantly increased CD4 positive cells and CD4:CD8 ratio of 1.8. The immune cell infiltrate of early morphea was enriched in CXCR3+ immune cells. CXCR3 co-localizes with CD4+ cells, but not CD8+ lymphocytes. We demonstrate that CXCL9 is expressed by a small subset of cells of varying morphologies within perivascular, periadnexal, and interstitial infiltrates. CXCL9 expression co-localized with CD68, but not CD20, CD34, CD123, or SMA, suggesting that dermal macrophages may secrete CXCL9 ligand. Moreover, CXCL9 expression was detected in close proximity to CXCR3 expressing immune cells. Based on our findings, we suggest that macrophage expression of CXCR3 ligands, specifically CXCL9, in morphea may enhance recruitment of CXCR-3 expressing activated T lymphocytes into the lesional skin and propagate early stages of inflammation.