Human Dermal Fibroblasts from Systemic Lupus Erythematosus (SLE) Patient

SLE Dermal Fibroblasts Exhibit Hyperinflammatory Responses

Cutaneous lupus erythematosus (CLE) lesions endure chronic inflammation; however, the mechanisms by which inflammation leads to either scarring or non-scarring disease pathology remain unclear. To gain insight into fibroblast-intrinsic mechanisms that may contribute to tissue pathology, Shoffner-Beck et al. compared cytokine responses between non-lesional dermal fibroblasts isolated from patients with SLE/CLE versus healthy controls.

To examine fibroblast functional differences, they established cultures from punch biopsies of healthy control skin and nonlesional lupus skin (upper thigh, non-sun-exposed). Fibroblasts at passage 2 were treated with IFN-γ, IFN-α, TNF-α, TGF-β, or IL-1β (cytokines identified as upstream regulators of differences observed between healthy control and SLE fibroblasts from scRNA-Seq) for 6 h prior to RNA isolation (Fig. 1). Both groups were confirmed to have similar fibroblast populations prior to and after cytokine stimulation. Both healthy control and SLE fibroblasts had differentially expressed genes after cytokine stimulation. However, greatest differences in effect size between healthy and SLE fibroblasts were noted after treatment with TGF-β, TNF-α, IFN-γ, and IFN-α (Fig. 2A). Within cytokine-cytokine receptor signaling pathways, genes belonging to the CXCL family, CCL family, IL family, and TNF had significantly higher expression across all treatments with significantly greater magnitude in SLE fibroblasts (FDR < 1 × 10^-5; Fig. 2B). When focusing specifically on responses to TGF-β stimulation, there were significantly higher fold changes between SLE compared to healthy control fibroblasts (Fig. 2C). These data suggest that inflammatory cytokines induce signaling pathways in both healthy and SLE fibroblasts but that this response is exaggerated in SLE fibroblasts.