Molecular mapping of necrobiosis lipoidica for identification of disease mechanisms and novel therapeutic strategies
Journal of Investigative Dermatology(2018)
Abstract
Necrobiosis lipoidica (NL) is a chronic, disfiguring granulomatous skin disorder primarily involving lower legs. Although associated with diabetes, the etiology and mechanisms underlying NL are unknown and treatment remains challenging. We hypothesized that comprehensive characterization of the RNA transcriptome in NL may increase the understanding of the underlying processes and highlight possible therapeutic opportunities. A total of 18 representative NL tissues and 5 normal skin tissues were subjected to next generation RNA sequencing. In addition, independent validation was performed using Nanostring panel (594 immune-specific genes), demonstrating high concordance in the set of genes identified as differentially expressed by both platforms, notably highly enriched for immune system genes. We assessed the composition of the immune cell population in NL using CIBERSORT analysis, a tool that predicts relative abundances of 22 immune cell types based on mRNA expression of cell-specific markers, and noted a significant (p<0.01) increase in M0 macrophages and decrease in mast cells within NL tissues. We also characterized processes and pathways differentially activated in NL, pointing out a set of immune pathways (inflammasome pathway, TREM1 signaling, interferon signaling, iCOS-iCOSL signaling) and also diabetes signaling. Finally, we mapped likely upstream regulators (including IFNG, TNF, NFkB, IL1R) and linked key genes in the identified networks to a spectrum of potential existing therapeutic options. We here provide first comprehensive transcriptional map of NL, define the spectrum of involved processes and signaling networks and link this molecular data to a set of therapeutics that may offer treatment options beyond those historically deployed in NL.
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Key words
necrobiosis lipoidica,molecular mapping,disease mechanisms
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