EGFR-STAT1 pathway drives fibrosis initiation in fibroinflammatory skin diseases

Chronic inflammatory skin diseases affect the health of millions of people worldwide, and those that feature fibrosis are refractory to treatments. The signals that determine whether fibrosis occurs during chronic skin inflammation are poorly understood. We generated a scRNA-seq atlas of seven inflammatory skin diseases and their healthy controls. Diseases with fibrosis demonstrate higher expression and activity of STAT1 in fibroblasts. Fibroblast STAT1 is required for skin fibrosis development in mice. STAT1 activation promotes a fibrotic gene expression profile which can be activated directly by EGFR in a JAK-independent manner and abrogated by genetic and pharmacologic STAT1 inhibition. The EGFR-STAT1 pathway is stimulated by high affinity EGFR ligands expressed by activated keratinocytes, suggesting keratinocyte-derived signals as triggers of skin fibrosis. In sum, fibroinflammatory skin diseases are characterized by fibroblast EGFR-STAT1 signaling that controls expression of fibrotic genes, elucidating an interferon independent function of STAT1 to mediate fibrotic skin diseases.