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

Author:

Odell Ian D.12ORCID,Steach Holly2ORCID,Gauld Stephen B.3ORCID,Reinke-Breen Lauren3,Karman Jozsef3,Carr Tracy L.3,Wetter Joseph B.3,Phillips Lucy3,Hinchcliff Monique4,Flavell Richard A.25ORCID

Affiliation:

1. Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.

2. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.

3. AbbVie Inc., North Chicago, IL, USA.

4. Department of Internal Medicine, Section of Rheumatology, Allergy and Immunology, Yale School of Medicine, New Haven, CT, USA.

5. Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Abstract

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. We found that epiregulin expression marks an inducible state of DC3 dendritic cells triggered by type I interferon and that DC3-derived epiregulin activates EGFR on fibroblasts, driving a positive feedback loop through NOTCH signaling. In 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. Therapeutic administration of epiregulin antibody reversed fibrosis in patient skin and lung explants, identifying it as a previously unexplored biologic drug target. Our findings reveal epiregulin as a crucial immune signal that maintains skin and lung fibrosis in multiple diseases and represents a promising antifibrotic target.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine,Immunology

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