Cutaneous lupus erythematosus (CLE) is a disfiguring and common manifestation in systemic lupus erythematosus (SLE), and the etiology of this predisposition for cutaneous inflammation is unknown. Here, we sought to examine the keratinocyte as an important source of IL-6 and define the mechanism for its increased production in CLE. Evaluation of discoid and subacute cutaneous lupus erythematosus lesions revealed significant epidermal upregulation of IL-6 when compared with control via real-time PCR and immunohistochemistry. Keratinocytes from unaffected skin of lupus patients produced significantly more IL-6 compared with healthy controls following exposure to TLR2, 3, or 4 agonists, or exposure to UVB radiation. Importantly, pretreatment with type I interferons (IFNα and IFNκ) increased IL-6 production by control keratinocytes, and type I IFN blockade decreased IL-6 secretion by lupus keratinocytes. Secretion of keratinocyte-specific IFNκ was significantly increased after TLR2 and UVB treatment in lupus keratinocytes and neutralization of IFNκ decreased IL-6 production by lupus keratinocytes. Thus, lupus keratinocytes are primed for IL-6 hyper-production in a type I IFN-dependent manner. Increased production of IFNκ by lupus keratinocytes drives this response, indicating that IFNκ may play a pathogenic role in CLE and serve as a novel target for treatment.

Cutaneous lupus erythematosus (CLE) is a common manifestation of systemic lupus erythematosus (SLE), and CLE can also develop without systemic involvement. CLE can be difficult to treat and negatively contributes to quality of life. Despite the importance of CLE, our knowledge of what differentiates cutaneous lupus subtypes is limited. Here, we utilized a large cohort of 90 CLE lesional biopsies to compare discoid lupus erythematosus (DLE) and subacute cutaneous lupus (SCLE) in patients with and without associated SLE in order to discern the drivers of disease activity and possibly uncover better treatment targets. Overall, we found that DLE and SCLE share many differentially expressed genes (DEG) reflecting type I interferon (IFN) signaling and repression of EGFR pathways. No differences between CLE only and SLE-associated CLE lesions were found. Of note, DLE uniquely expresses an IFN-γ node. Unbiased cluster analysis of the DEGs identified two groups separated by neutrophilic vs. monocytic signatures that did not sort the patients based on clinical phenotype or disease activity. This suggests that unbiased analysis of the pathobiology of CLE lesions may be important for personalized medicine and targeted therapeutic decision making.

Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease characterized by a diverse cadre of clinical presentations. CLE commonly occurs in patients with systemic lupus erythematosus (SLE), and CLE can also develop in the absence of systemic disease. Although CLE is a complex and heterogeneous disease, several studies have identified common signaling pathways, including those of type I interferons (IFNs), that play a key role in driving cutaneous inflammation across all CLE subsets. However, discriminating factors that drive different phenotypes of skin lesions remain to be determined. Thus, we sought to understand the skin-associated cellular and transcriptional differences in CLE subsets and how the different types of cutaneous inflammation relate to the presence of systemic lupus disease. In this study, we utilized two distinct cohorts comprising a total of 150 CLE lesional biopsies to compare discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), and acute cutaneous lupus erythematosus (ACLE) in patients with and without associated SLE. Using an unbiased approach, we demonstrated a CLE subtype-dependent gradient of B cell enrichment in the skin, with DLE lesions harboring a more dominant skin B cell transcriptional signature and enrichment of B cells on immunostaining compared to ACLE and SCLE. Additionally, we observed a significant increase in B cell signatures in the lesional skin from patients with isolated CLE compared with similar lesions from patients with systemic lupus. This trend was driven primarily by differences in the DLE subgroup. Our work thus shows that skin-associated B cell responses distinguish CLE subtypes in patients with and without associated SLE, suggesting that B cell function in skin may be an important link between cutaneous lupus and systemic disease activity.

IL-10 interferes with endothelial differentiation and may enhance the effects of type I IFN on vascular repair in SLE. IL-10 may be a relevant target for improving cardiovascular risk in SLE.