Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis

Immune cells are fundamental regulators of extracellular matrix (ECM) production by fibroblasts and have important roles in determining extent of fibrosis in response to inflammation. Although much is known about fibroblast signaling in fibrosis, the molecular signals between immune cells and fibroblasts that drive its persistence are poorly understood. We therefore analyzed skin and lung samples of patients with diffuse cutaneous systemic sclerosis, an autoimmune disease that causes debilitating fibrosis of the skin and internal organs. Here we define a critical role of epiregulin – EGFR signaling between dendritic cells and fibroblasts to maintain elevated ECM production and accumulation in fibrotic tissue. Mechanistic studies demonstrate that epiregulin expression marks an inducible state of DC3 dendritic cells triggered by type I interferon. DC3-derived epiregulin activates EGFR on fibroblasts, which drives a positive feedback loop through NOTCH signaling. In well-established mouse models of skin and lung fibrosis, epiregulin was essential for persistence of fibrosis in both tissues, which could be abrogated by epiregulin genetic deficiency or a neutralizing antibody. Notably, therapeutic administration of epiregulin antibody reversed fibrosis in patient skin and lung explants, identifying it as a novel biologic drug target. Our findings reveal epiregulin as a crucial immune signal that maintains skin and lung fibrosis in multiple diseases and is a highly promising antifibrotic target. Skin biopsies from 5 patients with scleroderma (SSc1-5) and 6 healthy controls (Normal1-6) were analyzed using 10x genomics platform