MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that regulate the gene expression at a post-transcriptional level and participate in maintaining the correct cell homeostasis and functioning. Different specific profiles have been identified in lesional skin from autoimmune cutaneous diseases, and their deregulation cause aberrant control of biological pathways, contributing to pathogenic conditions. Detailed knowledge of microRNA-affected pathways is of crucial importance for understating their role in skin autoimmune diseases. They may be promising therapeutic targets with novel clinical implications. They are not only present in skin tissue, but they have also been found in other biological fluids, such as serum, plasma and urine from patients, and therefore, they are potential biomarkers for the diagnosis, prognosis and response to treatment. In this review, we discuss the current understanding of the role of described miRNAs in several cutaneous autoimmune diseases: psoriasis (Ps, 33 miRNAs), cutaneous lupus erythematosus (CLE, 2 miRNAs) and atopic dermatitis (AD, 8 miRNAs). We highlight their role as crucial elements implicated in disease pathogenesis and their applicability as biomarkers and as a novel therapeutic approach in the management of skin inflammatory diseases.

Thalidomide is effective in patients with refractory cutaneous lupus erythematosus (CLE). However, the mechanism of action is not completely understood, and its use is limited by its potential, severe side-effects. Immune cell subset analysis in thalidomide’s CLE responder patients showed a reduction of circulating and tissue cytotoxic T-cells with an increase of iNKT cells and a shift towards a Th2 response. We conducted an RNA-sequencing study using CLE skin biopsies performing a Therapeutic Performance Mapping System (TMPS) analysis in order to generate a predictive model of its mechanism of action and to identify new potential therapeutic targets. Integrating RNA-seq data, public databases, and literature, TMPS analysis generated mathematical models which predicted that thalidomide acts via two CRBN-CRL4A- (CRL4^CRBN) dependent pathways: IRF4/NF-ҡB and AMPK1/mTOR. Skin biopsies showed a significant reduction of IRF4 and mTOR in post-treatment samples by immunofluorescence. In vitro experiments confirmed the effect of thalidomide downregulating IRF4 in PBMCs and mTOR in keratinocytes, which converged in an NF-ҡB reduction that led to a resolution of the inflammatory lesion. These results emphasize the anti-inflammatory role of thalidomide in CLE treatment, providing novel molecular targets for the development of new therapies that could avoid thalidomide’s side effects while maintaining its efficacy.