© 2018 The Authors Cutaneous lupus erythematosus is a common and disfiguring manifestation in systemic lupus erythematosus. Subacute cutaneous lupus erythematosus and discoid lupus erythematosus (DLE) are the most prevalent forms. Despite sharing histological similarities, clinically they differ in their course and prognosis, suggesting different pathogenesis. Here, we show that DLE-affected skin has a specific microRNA expression profile when compared with subacute cutaneous lupus erythematosus. Among the DLE-specific microRNAs, we identified one keratinocyte-derived microRNA, miR-31, and one leukocyte-derived microRNA, miR-485-3p. We show that UV and transforming growth factor-β1 stimulation up-regulates miR31 expression in DLE. Specific miR-31 overexpression induces keratinocyte apoptosis and NF-κB pathway activation with the production of related inflammatory cytokines and contributes to the recruitment of neutrophils and intermediate monocytes at the inflammation site. IL-1α and TGF-β1 stimulation increased the expression of miR-485-3p in peripheral mononuclear blood cells from DLE patients and induced T-cell activation, mainly of CD8 lymphocytes. In addition, miR-485-3p overexpression in dermal fibroblasts contributes to fibrosis by targeting peroxisome PGC-1α. Collectively, our findings suggest that overexpression of miR-31 and miR-485-p contribute to skin inflammation in DLE lesions by regulating the production of inflammatory mediators and attracting neutrophils and intermediate monocytes to the skin.