Molecular Profiling of Cutaneous Lupus Lesions Identifies Subgroups Distinct from Clinical Phenotypes

Abstract

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.

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

“…The role of IL17A in regulating granulopoiesis and neutrophil recruitment via induction of G-CSF is well recognized under homeostatic conditions 34,70 and a few studies have identified IL17-A as important for neutrophil recruitment to the sites of sterile inflammation 71,72 . In lupus, elevated IL-17A expression is found in cutaneous lesions 73,74 and increased circulating IL-17A levels have been associated with worse disease manifestations 75,76 , although the specific relationship to neutrophils, a pathogenic population in this disease, 11,[15][16][17] remains unexplored. Besides its direct effects on G-CSF-mediated mobilization of neutrophils from the bone marrow, IL-17A may also contribute to neutrophil homing to the kidney by stimulating expression of adhesion molecules (e.g.…”

“…In SLE, a neutrophil gene signature is a strong predictor of active disease including LN and cutaneous lupus [15][16][17] . Neutrophils are found in cutaneous lesions [10][11][12] as well as kidney biopsy specimens 13,14 of SLE patients and their inflammatory properties have been attributed to NET formation 14,21 . This process includes increased production of ROS 19,82 , mitochondrial DNA release 19 , as well as release and induction of inflammatory proteins such as s100A9 83 , IL-1b 84 , and type I interferons 19,85,86 .…”

“…While both the aged (CXCR4 hi ) and the reverse migrating (ICAM1 hi CXCR1 lo ) neutrophil phenotypes have been associated with inflammatory functions and tissue injury in different murine models 51,52,60 , few studies have been performed on these cell populations in human disease. Given the emerging role of neutrophils in SLE 11,[15][16][17] and their apparent heterogeneity 18 , we investigated whether PMNs or low density granulocytes (LDGs) 64,65 from SLE patients demonstrated the phenotypes of aged, CXCR4 hi , or reverse migrating, ICAM1 hi CXCR1 lo , neutrophils. Flow cytometry profiling of PMNs and LDGs revealed higher CXCR4 expression on the surface of these cells in SLE patients, compared to healthy controls ( Fig.…”

“…Recent findings indicate that neutrophils play an important role in both local and systemic lupus disease. Neutrophils are present in the skin lesions of SLE patients [10][11][12] as well as in the kidney tissue of patients with LN 13,14 . High expression of a neutrophil gene signature is a strong predictor of active SLE, including nephritis and cutaneous flares [15][16][17] .…”

Staphylococcus aureus Colonization Is Increased on Lupus Skin Lesions and Is Promoted by IFN-Mediated Barrier Disruption

“…However, barrier gene expression in cutaneous lupus erythematosus is not well understood. Thus, we compared normalized data from microarray analysis of SLE lesional skin versus HC skin (Gene Expression Omnibus accession number GSE81071) (Berthier et al, 2019). Expectedly, IFN-stimulated genes and IFNs including IFN-k, a regulator in keratinocytes for type I responses, were elevated significantly in cutaneous lupus lesions (1.53-fold change; q ¼ 0.0006).…”