Lupus fibroblasts hyperrespond to inflammatory cytokines and upregulate pro-fibrotic collagens in patients with scarring skin lesions

Cutaneous lupus erythematosus (CLE) is a manifestation of systemic lupus erythematosus (SLE) that can cause significant patient distress due to scarring. Mechanisms of scarring remain poorly understood and interventions for prevention and treatment are lacking. Fibroblasts (FBs) are involved in inflammation and scarring, yet the role of inflammatory mediators on FB function in SLE is unclear. In this study, we examined the inflammatory phenotype in FBs isolated from non-lesional skin punch biopsies from healthy controls (HC) (n=34), and SLE patients with (n=8) and without (n=13) scarring disease. Cytokine-cytokine receptor signaling pathway genes were differentially expressed across all conditions, with exaggerated upregulation in SLE FBs in comparison to HC (log2FC>0.6 and p<0.05). Pathway analysis revealed upregulation of pro-inflammatory pathways in non-scarring disease relative to scarring disease, including CXCL, CCL, and interleukin genes, especially after stimulation with TGF-β, a known fibrotic factor involved in myofibroblast activation. Scarring patients had upregulation of collagen trimer pathway genes, including COL17A1, especially after stimulation with TNF-α or TGF-β. Histologic confirmation of collagen staining identified pro-fibrotic collagen expression in scarring skin lesions, near inflammatory infiltrates. Our results show that exposure to inflammatory cytokines leads to exaggerated upregulation of pro-inflammatory pathways in SLE fibroblasts in comparison to HC and, while all SLE fibroblasts are associated with elevated inflammation, FBs from patients who scar are associated with upregulation of collagen pathways. These results provide important insights into the mechanisms of scarring in CLE and potential targets for intervention.