045 An EGFR ligand maintains scleroderma skin and lung fibrosis

I. Odell, H. Steach,S. Gauld,T. Carr, J. Wetter, L. Phillips,M. Hinchcliff,R. Flavell

Journal of Investigative Dermatology(2022)

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Abstract
Systemic sclerosis (SSc/scleroderma) is an autoimmune disease that causes skin and internal organ fibrosis. Molecular signals that regulate the persistence of fibrosis are poorly understood. In SSc skin, Epidermal Growth Factor Receptor (EGFR) ligand expression correlates with skin fibrosis severity. However, EGFR inhibition has shown inconsistent results in fibrosis mouse models. We hypothesized that an immune-mesenchymal signaling circuit underlies SSc-related skin and lung fibrosis, and that targeting a specific EGFR ligand may prevent receptor activation on pathologic fibroblasts. Through scRNA-Seq of skin and lung tissues from patients with diffuse cutaneous SSc, we identified EGFR activation as a marker of pathogenic fibroblasts in both organs. Examination of ligand-receptor enrichment identified a unique dendritic cell-derived EGFR ligand as a driver of fibroblast EGFR activation. In mice, this ligand was essential for the persistence of skin and lung fibrosis, and its inhibition with a neutralizing antibody resulted in complete normalization of dermal skin thickness, 50% reduction in collagen content, and 190% reduction in Col1a1 expression (to below control levels). In the lungs, EGFR ligand inhibition led to a 2-point reduction in modified Ashcroft score and 38% reduction in collagen content. We further validated the antibody on lung explants from a patient with idiopathic pulmonary fibrosis, which reduced collagen secretion and expression by 56% and 70%, respectively. Mechanistically, this EGFR ligand signals downstream of type I interferon to drive a multicellular circuit, in which EGFR induces NOTCH activation and excess extracellular matrix production by fibroblasts. Since antibody patent is pending, target withheld until meeting. Our findings reveal an EGFR ligand as a crucial signal that maintains skin and lung fibrosis in SSc and other fibrotic diseases.
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Key words
egfr ligand,scleroderma skin
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