Background/Purpose: Thy-1 (CD90) is a GPI-anchored cell surface protein that is highly expressed in subsets of fibroblasts. Previous work has shown that Thy-1 deficiency exacerbates lung fibrosis. In inflammatory arthritis, Thy-1 marks a subset of pathogenic fibroblasts. Thy-1 is overexpressed in skin of patients with systemic sclerosis (SSc), and we previously showed that Thy-1 can serve as an in vivo marker of cutaneous fibrosis progression, but its role in pathogenesis remains unclear. This study focuses on the effect of Thy-1’s modulation of cutaneous fibrosis.

Methods: To induce fibrosis, Thy-1 deficient mice were treated with subcutaneous bleomycin or crossed with TSK1 mice. Mice were fed chow or high fat diet for 12 weeks before starting bleomycin injections. Bleomycin time-course experiments were performed and skin was harvested at days 5, 12, 21, 35 and 52 and was processed for histology, qPCR and immunohistochemical staining. RNA sequencing was performed on affected skin from both wildtype and Thy-1 null mice treated either with bleomycin or PBS (n=12). Differential gene expression analysis was performed using deSeq2, and pathway analysis was performed using Enrichr. To assess Thy-1’s role in SSc severity, Thy-1 expression was correlated to modified Rodnan skin score (MRSS) in publicly available datasets.

Results: Skin biopsies from SSc patients have elevated expression of Thy-1 compared to healthy controls (p< 0.0001). Patients with diffuse cutaneous and early disease have increased Thy-1 expression (p< 0.001), and this is associated with severity of skin involvement (Spearman 0.63, p< 0.0001).  Mice lacking Thy-1 show protection from chemically-induced and genetically-mediated cutaneous fibrosis at both the histologic and biochemical levels. Fibrosis was attenuated in the Thy-1 null mice with a ~65% reduction in dermal thickness. While wildtype mice demonstrated resolution of fibrosis by later time-points, Thy-1 null mice showed a defective resolution response implicating different mechanisms of Thy-1 in early and late stages of fibrosis. RNA-seq clustering analysis differentiated control and bleomycin-treated Thy-1 null from wildtype mice. Bleomycin upregulated leukocyte chemotaxis, inflammatory response, and muscle contraction pathways regardless of genotype. In Thy-1 null mice, bleomycin specifically upregulated IL-17 and TNF pathways. Fatty acid metabolism pathways were the main feature that distinguished Thy-1 null from control mice treated with bleomycin. However, feeding Thy-1 null mice a high fat diet did not alter their anti-fibrotic phenotype.

Conclusion: Thy-1 expression is increased in SSc and associated with severity of skin involvement. In complementary murine models of cutaneous fibrosis, Thy-1 deficiency has an anti-fibrotic effect which appears to be mediated by TNF, IL-17 and fatty acid metabolism. Thy-1 appears to have different effects on the temporal stages of fibrosis indicating that targeting Thy-1 early in disease may be a rational approach.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-role-of-thy-1-cd90-in-the-pathogenesis-of-skin-fibrosis/